PT2180882E - Solid matrix pharmaceutical preparation - Google Patents

Description

DESCRIPTION

SOLID PHARMACEUTICAL PREPARATION OF MATRIX TECHNICAL FIELD The present invention relates to a solid pharmaceutical preparation.

PREVIOUS TECHNIQUE

There have been many attempts in the medical field to control the release of drugs and maintain the concentration of the drug in the blood at an appropriate level over a long period of time. To maintain the concentration of the drug in the blood at an appropriate level over a long period of time, it is necessary to maintain drug absorption over a long period of time to utilize the pharmaceutical (sustained release techniques) capabilities. Solid preparations given orally move from the upper gastrointestinal tract (stomach and upper small intestine) to the lower part (lower small intestine and large intestine) as time goes by; the absorption capacity of the drug is often lower in the lower part of the gastrointestinal tract than in the upper part. Therefore, it is considered of utmost importance to develop a strategy whereby the drug can be absorbed continuously in the lower gastrointestinal tract, where the solid preparation remains for a longer period of time.

Known sustained release techniques include, for example, a sustained release technique 1 which is based on diffusion control, i.e., membrane coated preparations, wherein the core compositions or the core tablets contain drugs coated with polymer films insoluble in water; matrix preparations produced together with water-insoluble polymers, waxes, etc .; and the like. However, with these techniques, since the rate of drug release decreases as the release progresses, the rate of drug release is deficient in the lower gastrointestinal tract, where the preparation reaches several hours after administration. As a result, the concentration of drug in the blood is difficult to maintain.

Another known sustained release technique adopts the pharmaceutical approach designed to deliver the drug into the lower gastrointestinal tract (for example, enteric coated preparations in which the immediate release and drug-containing core compositions are coated with enteric films). However, this technique controls the release of the drug with films and therefore requires a coating procedure with a film. As a result, the production process of the pharmaceutical preparation becomes complicated.

On the other hand, sustained release matrix preparations are known and are produced using enteric methacrylic acid based polymers. The enteric polymer becomes an insoluble substance in a pH range less than the pH at which the enteric polymer can be dissolved and becomes a soluble substance in a range of pH above the pH at which the enteric polymer can be dissolved. Therefore, the matrix preparation containing an enteric polymer can suppress drug release in the upper gastrointestinal tract and rapidly release the drug into the lower gastrointestinal tract. In other words, the pH sensitive response of the enteric polymer enables the provision of sustained release preparations with precisely controlled release of the drug.

For example, patent documents 1, 2, 3 and 4 describe matrix preparations containing an enteric polymer obtained by mixing an enteric polymer and a drug, followed by compaction (tablet compression). However, while the drug release from the matrix preparations is generally considered to be dependent on the surface area of the pharmaceutical preparation, such matrix preparations obtained by compressing the tablets have a small surface area in contact with a solvent. For poorly soluble drugs with a slow dissolution rate, the small surface area of the pharmaceutical preparation induces deficiencies in drug release.

In contrast, patent document 5 describes preparations obtained by wet grinding of a powder blend containing an S copolymer of methacrylic acid with ethanol, followed by extrusion. This preparation is formed of sustained release pellets by wet grinding and extrusion. Such preparation (pellets, granules and powders are referred to as multi-unit type preparations) may have a larger surface area and also applies to poorly soluble drugs. In addition, when compared to single unit type preparations such as tablets obtained by tabletting, multi-unit type preparations such as pellets are sparingly dispersed in the gastrointestinal tract. Therefore, such pellets can reduce the inter-entity variance in the absorption of the drug from the tablets. Patent document 6 relates to multiple particles having controlled release properties which are substantially free of lubricant. The multiple particles are obtained by extruding a mixture containing a pharmaceutically active agent in which a plasticizer is used in an amount sufficient to act as a plasticizer and also as a lubricant. Patent document 7 relates to multiple oxycodone particles which may be prepared by extruding a mixture which suitably comprises (a) oxycodone, (b) water insoluble ammonium methacrylate copolymer, (c) plasticizer, (d) lubricant and (e) water permeability modifier. Patent document 8 relates to a neutral copolymer of poly (ethyl acrylate, methyl methacrylate) which is used as a carrier in the manufacture of pharmaceutical formulations containing an active ingredient. Patent document 9 relates to compositions coated with a sustained release gel wherein the gel coating comprises a pharmaceutically acceptable mixture of gelatin and hydrophobic polymer.

In addition, the non-patent document 1 describes multi-unit type preparations comprising methacrylic acid copolymer S, methacrylic acid copolymer LD, a drug, polyvinylpyrrolidone and 4-triethyl citrate as plasticizer. The preparations are obtained by wet grinding with water, followed by extrusion and spheronization.

Patent Document 1: Japanese Patent Laid-Open Publication No. 1992-43049

Patent Document 2: Japanese Unexamined Patent Publication No. 1994-199657

Patent Document 3: U.S. Patent 4,968,508 Patent Document 4: U.S. Pat. 2006-0259753

Patent Document 5: Japanese Unexamined Patent Publication No. 1994-24991

Patent Document 6: WO 2006/024881 A

Patent Document 7: WO 2005/000310 A

Patent Document 8: WO 2005/079760 A

Patent Document 9: WO 03/082204 A

Non-Patent Document 1: International Journal of Pharmaceutics, 2001, vol. 213, p. 7-12

DESCRIPTION OF THE INVENTION

However, as described below, there are problems in the process which produces pellets or granules by treating a mixture containing the above-mentioned enteric polymer by extrusion and spheronization.

First, the methacrylic acid-based enteric polymer is a strong enteric polymer, as expected, considering its high glass transition temperature of not less than 160 ° C. For this reason, when the matrix preparations containing methacrylic acid-based enteric polymers are produced by extrusion and spheronization, the wet-milled product should be complimented with plasticity so that the extrusion can be performed smoothly.

While the proportion of the methacrylic acid copolymer S in the pharmaceutical composition prepared by the process of Patent Document 5 is 5% by weight, the amount of methacrylic acid copolymer S in the composition should be increased in order to increase the pH response of the preparation obtained. However, the increased amount of methacrylic acid copolymer S in the composition results in insufficient plasticity, making it difficult to produce matrix preparations containing methacrylic acid-based enteric polymers by the extrusion and spheronization process. More specifically, such insufficient plasticity increases the strength when extruding the comminuted product in a wet medium. As a result, extrusion can not be performed.

On the other hand, the pharmaceutical composition prepared by the technique of non-patent document 1 containing 77% by weight of the methacrylic acid copolymer and about 11% by weight of triethyl citrate is added as plasticiser to complement plasticity required for the extrusion of a wet milled product. However, with this technique, the glass transition temperature of the enteric polymer based on methacrylic acid is reduced due to the addition of a plasticizer, resulting in the metamorphosis and deformation of the enteric polymers, based on methacrylic acid. Accordingly, a film may be formed within the screen die of the extrusion machine which eventually causes clogging or failure. Furthermore, the metamorphosis and deformation over time of the enteric polymers based on methacrylic acid and the change in dissolution of the preparations obtained over time may possibly result because of the plasticizer remaining in the preparations obtained. In addition, the prior art document 1 technique is concerned with drug incompatibility.

Thus, a plasticizing agent is required to increase the proportion of the enteric polymer based on methacrylic acid in the preparation obtained by extrusion, while the addition of a plasticizer causes unavoidable problems, as described above. In other words, it is quite difficult to increase the proportion of the enteric polymer in the preparation obtained by extrusion, while solving the problems resulting from the addition of a plasticizer. The present invention provides a solid pharmaceutical preparation which does not have the problems of the conventional techniques described above, although the composition ratio of the methacrylic acid-based enteric polymer composition with good pH response is increased to give the preparation sustained release properties.

More specifically, it is an object of the present invention to provide solid matrix-like preparations which overcome all previous problems caused by the addition of a plasticizer, while exhibiting advanced release controllability capable of suppressing drug release in the upper gastrointestinal tract and immediately release the drug into the lower gastrointestinal tract. The inventor has carried out extensive research to solve the above problems and has found that the desired solid matrix type preparations can be obtained by a combination of an enteric polymer based on methacrylic acid and a sugar and / or sugar alcohol with a specific property. The present invention has been made on the basis of these findings. The present invention provides a solid pharmaceutical preparation of the matrix type, as defined below in items 1 to 13.

Item 1: The solid pharmaceutical preparation of the matrix type comprises: (a) an enteric polymer based on methacrylic acid; and (b) a sugar and / or a sugar alcohol, wherein 1 g of sugar and / or sugar alcohol (b) may be dissolved in not more than 4 g of water, at a temperature of water between 20 and 25 ° C.

Item 2: The solid pharmaceutical preparation according to item 1 wherein the amount of sugar and / or sugar alcohol is 0.1 to 10 parts by weight based on 1 part by weight of the enteric polymer based of methacrylic acid.

Item 3: The solid pharmaceutical preparation according to item 1 or 2, wherein the sugar and / or sugar alcohol has a melting point of 140 ° C or lower.

Item 4: The solid pharmaceutical preparation, according to item 1 or 2, free of plasticizer.

Item 5 The solid pharmaceutical preparation, according to item 3, is free of plasticizer.

Item 6: The solid pharmaceutical preparation according to item 1 or 2, prepared by a production process, including an extrusion process.

Item 7 The solid pharmaceutical preparation according to item 3, prepared by a production process, including an extrusion process.

Item 8: The solid pharmaceutical preparation according to any one of items 1 to 7, wherein the sugar and / or sugar alcohol has at least one element selected from the group consisting of erythritol, xylitol, lactitol, sorbitol, trehalose and maltose, dextrose, fructose and maltitol.

Item 9: The solid pharmaceutical preparation according to item 1, wherein the content of the enteric polymer based on methacrylic acid is 6 to 50% by weight.

Item 10: The solid pharmaceutical preparation according to item 1, wherein the methacrylic acid-based enteric polymers dissolve with the dissolution property being pH 5.5 or higher.

Item 11: The solid pharmaceutical preparation according to item 1, wherein the methacrylic acid-based enteric polymers have a glass transition temperature of not less than 100 ° C.

Item 12: The solid pharmaceutical preparation according to any one of items 1 to 11, wherein the methacrylic acid-based enteric polymer is at least one member selected from the group consisting of the copolymer L of methacrylic acid, methacrylic acid copolymer and methacrylic acid copolymer S. 9

Item 13: The solid pharmaceutical preparation according to item 1, comprising a drug selected from the group consisting of cilostazol, tolvaptan, phenytoin, aspirin and naproxen.

Solid Pharmaceutical Preparation The solid pharmaceutical preparation of the matrix type of the present invention comprises (a) an enteric polymer based on methacrylic acid and (b) a sugar and / or a sugar alcohol. The sugar and / or sugar alcohol (b) have the property that 1 g of that product can be dissolved in not more than 4 g of water at a time when the water temperature is between 20 and 25 ° C. The solid pharmaceutical preparation of the present invention may contain other components, preferably (c) a drug and (d) a form-maintaining material in addition to the components referred to in (a) and (b) above. The solid pharmaceutical preparation does not contain a plasticizer. The solid pharmaceutical preparation is preferably a sustained oral release matrix type pharmaceutical solid preparation. (a) Enteric polymer based on methacrylic acid

In the present invention, a wide range of known methacrylic acid-based enteric polymers can be used as the methacrylic acid-based enteric polymer (a) provided they are soluble at an ambient pH of the small intestine and large intestine. Suitable enteric methacrylic acid-based polymers 10 are dissolved at a pH of 5.5 or higher, more preferably 6.0 and at a pH of 7.5 or less. When the dissolution pH is within this range, the enteric polymer dissolves in the small intestine and / or the large intestine, which allows for rapid release of the drug from the preparation into the lower gastrointestinal tract.

Further, in the present invention, the glass transition temperature of the methacrylic acid-based enteric polymer is generally 100øC or greater, preferably 105øC or greater, more preferably 130øC or higher. The glass transition temperature is preferably 200 ° C or lower. At the glass transition temperature, in this range, no deformation or metamorphosis occurs at room temperature, leading to less concern with a change in the dissolution of the preparation, over time. Another advantage is that the extrusion can be carried out without the imposition of an excessive load on the extruder.

Specific suitable examples of the methacrylic acid-based enteric polymer include methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer S and the like. The copolymer LD of methacrylic acid preferably takes the form of powders. The copolymer LD powder of methacrylic acid indicates a polymer which is neither in liquid form nor in the form of a suspension having a solids content of 30%. In addition, the methacrylic acid copolymer LD to be used in the present invention may be in an anhydrous state or, even when it has some moisture, is in powder form. Hereinafter, this LD copolymer of powdered methacrylic acid is occasionally referred to as an LD copolymer of anhydrous methacrylic acid. 11

As enteric polymers based on methacrylic acid, any commercially available products can be readily used. For example, " Eudragit L100D55 " (Degussa AG) can be used as LD copolymer of anhydrous methacrylic acid, " Eudragit L100 " (Degussa AG) as copolymer L of methacrylic acid and " Eudragit S100 " (Degussa AG), as copolymer S of methacrylic acid, respectively. These enteric polymers may be used alone or in combination of two or more.

By mixing two or more of such enteric polymers, a pH value in the range of 5.5 to 7 can be arbitrarily determined in which the preparation dissolves in the lower part of the small intestine and in the large intestine (dissolution pH of the enteric polymer). For example, when the dissolution pH of the enteric polymer is arbitrarily determined in the range of 5.5 to 6, the mixing ratio between methacrylic acid copolymer LD and methacrylic acid copolymer L may be in the range of 1:99 to 99: 1. In addition, when the dissolution pH of the enteric polymer is determined arbitrarily in the range of 5.5 to 7, the blend ratio of copolymer LD of methacrylic acid and methacrylic acid copolymer S may be in the range of 1:99 to 99: 1. Still further, when the dissolution pH of the enteric polymer is determined arbitrarily in the range of 6 to 7, the blend ratio of copolymer L of methacrylic acid to copolymer L of methacrylic acid may be in the range of 1:99 to 99: 1.

In the present invention, the amount of enteric polymer which is to be contained in the preparation is generally from 1 to 50% by weight, preferably 3 to 45% by weight, more preferably 6 to 40% by weight and even more preferably 10 to 35% by weight. The content of the enteric polymer 12 in this range is preferred in terms of the diversity of drug release patterns and the suitability of the production (excellent extrusion). Here, the variety of drug delivery standards means that one who devises the preparation can easily achieve a desired pattern of drug release. The methacrylic acid-based enteric polymer used for the solid pharmaceutical preparation of the present invention is preferably dissolved at a pH of 5.5 or higher. The pH response to be given to the solid pharmaceutical preparation of the present invention is suitably adjusted by the variety of drugs listed below, the desired pharmacological effects, etc. The pH response may also be adjusted by the variety of enteric polymer based methacrylic acid used, the amount of the enteric polymer contained in the preparation, etc.

For example, some preparations are preferably designed to slowly release the drugs in the upper gastrointestinal tract (in the stomach and upper small intestine), in addition to the function of the preparations being continuously absorbed in the lower gastrointestinal tract (lower part of the small intestine and large intestine ). In such cases, it is desirable to slow down the pH response of the solid pharmaceutical preparation. Specifically, the amount of methacrylic acid-based enteric polymer contained in the solid pharmaceutical preparation is set at a lower value. In addition, when the function of the preparation to be continuously absorbed in the lower gastrointestinal tract is enhanced, it is desirable to broaden the pH response of the solid pharmaceutical preparation. Specifically, the amount of methacrylic acid-based enteric polymer 13 contained in the solid pharmaceutical preparation is set at a higher value. (b) Sugar and / or sugar alcohol The sugar and / or sugar alcohol used in the present invention has a specific solubility in water. The amount of water at a water temperature between 20 and 25 ° C, necessary to dissolve 1 g of sugar and / or sugar alcohol is generally 4 g or less, preferably 3.5 g or less. In addition, the amount of water at a water temperature between 20 and 25 ° C, necessary to dissolve 1 g of sugar and / or sugar alcohol is desirably 1 g or more. When the amount of water required for dissolution is within this range, a plasticity can be provided to the comminuted mixture prior to production of the preparation.

More preferably, the sugar and / or sugar alcohol has a melting point of 140 ° C or lower, preferably 130 ° C or lower, more preferably 125 ° C or lower and 90 ° C or higher. With a melting point in this range, the sugar and / or sugar alcohol may take a solid form at room temperature, providing easy manipulation. Another advantage is that the hardness of the sugar and / or sugar alcohol has no effect on the extrusion. The sugar and / or sugar alcohol usable in the present invention may be those having such properties and may be in the form of a hydrate (s). Examples thereof include at least one element selected from the group consisting of erythritol, xylitol, lactitol, sorbitol, trehalose, maltose, dextrose, fructose or maltitol. 14

Preferably, examples thereof include at least one element selected from the group consisting of erythritol, xylitol, lactitol, sorbitol, trehalose, maltose, dextrose, fructose or maltitol. The most preferred sugars and / or sugar alcohols may be at least one element selected from the group consisting of erythritol, xylitol, lactitol, sorbitol, trehalose, maltose. Even more preferred sugars and / or sugar alcohols may be at least one member selected from the group consisting of erythritol, lactitol, trehalose monohydrate and dihydrate and maltose monohydrate. These sugars and / or sugar alcohols still more preferred have a reasonable solubility and an adequate melting point, as well as a lower concern with regard to hygroscopicity. They also have excellent storage stability over the long term. The sugar and / or sugar alcohol may be selected from a variety of commercial products. More specific examples are given below. (B-i) Erythritol and its hydrates Erythritol, i.e., a sugar alcohol, is produced from glucose by the reaction of an enzyme. The melting point of erythritol is 119 to 122øC and the amount of water (25øC) required to dissolve 1g of erythritol is 3.3g (Nikken Chemicals Co., Ltd., technical data of erythritol) . As erythritol, commercial products, such as " Erythritol 100M " (Nikken Chemicals Co., Ltd.). 15 (B-ii) Xylitol and its hydrates, xylitol, i.e., a sugar alcohol, is produced by the conversion of various cellulosic feedstock into xylose by hydrolysis, followed by hydrogenation. The xylitol has some hygroscopicity. The amount of water (20 ° C) required to dissolve 1 g of xylitol is 1.6 g (Handbook of Pharmaceutical Excipients, 2001, Japan Pharmaceutical Excipients Council). In addition, the melting point of xylitol is 93 to 95 ° C (Handbook of Pharmaceutical Excipients, 2001, Japan Pharmaceutical Excipients Council). As xylitol, commercial products, such as " xylitol P " (Nikken Fine Chemical Co., Ltd.), " XYLISORB " (Roquette) and " Xilit P " (Towa Chemical Industry Co., Ltd.). (B-iii) Lactitol and its hydrates Lactitol, i.e., a sugar alcohol, is produced by catalytic hydrogenation of lactose. Examples of lactitol include anhydride, monohydrate dihydrate and trihydrate. Among them, non-hygroscopic monohydrate is preferred. The melting point of lactitol monohydrate is 97øC (Merck Index, 12th edition) and the amount of water (20øC) required to dissolve 1g of lactitol is 1.8g (Handbook of Pharmaceutical Excipients , 2001, Japan Pharmaceutical Excipients Council). As lactitol monohydrate, commercial products, such as " Lactitol LC-1 " (Nikken Fine Chemicals Co., Ltd.). (B-iv) Sorbitol and its hydrates Sorbitol, that is, a sugar alcohol, is produced by subjecting glucose or corn syrup to hydrogenation, at high pressure or by electrolytic reduction. Sorbitol has high hygroscopicity. The amount of water (25øC) required to dissolve 1 g of sorbitol is 0.5 ml (g) (Handbook of Pharmaceutical Excipients, 2001, Japan Pharmaceutical Excipients Council). In addition, the melting point of sorbitol is 97 to 112Â ° C (Handbook of Pharmaceutical Excipients, 2001, Japan Pharmaceutical Excipients Council; Journal of Thermal Analysis and

Calorimetry, vol. 73, p. 615-621). As sorbitol, commercial products may be used, such as " Sorbitol SP " (Nikken Fine Chemical Co., Ltd.), " NEOSORB Powder " (Roquette) and " Sorbitol DP-10M " (Towa Chemical Industry Co., Ltd.). (B-v) Trehalose and its hydrates Trehalose dihydrate, i.e., a sugar component, is a disaccharide in which two glycoses are attached, similar to maltose. Trehalose, as a pharmaceutical additive, is produced from a partial starch degradation product by an enzymatic process using trehalose producing bacteria. Although the trehalose dihydrate is not hygroscopic, it has a low hygroscopicity. The melting point of the trehalose dihydrate is 97øC and the amount of water (20øC) required to dissolve 1g of trehalose dihydrate is 1.2g (technical data of trehalose, Hayashibara

Biochemical Labs., Inc.). As trehalose dihydrate, commercial products, such as " Trehalose P " (Asahi Kasei Chemicals Corp.) and " Treha " (Hayashibara Co., Ltd). (B-vi) Maltose and its hydrates Maltose monohydrate, i.e., a sugar component, is a disaccharide carbohydrate, which is produced by starch enzyme. When the maltose content is 90% or greater, it may also be used for pharmaceutical preparations as maltose syrup powder in a pharmaceutical additive. Maltose is divided into anhydride and monohydrate and the monohydrate has low hygroscopicity. The amount of water (20 ° C) required to dissolve 1 g of maltose monohydrate is 1.2 g (New Food Industry, Vol. 31, No. 4, pp. 17-22). In addition, the melting point (decomposition) of maltose monohydrate is 102 to 103Â ° C (Handbook of Pharmaceutical Excipients, 2001, Japan Pharmaceutical Excipients Council). As maltose monohydrate, commercial products, such as " Sunmalt-S " (Sanwa Cornstarch Co., Ltd.) and " Nisshoku crystalline maltose " (Nihon Shokuhin Kako Co., Ltd.).

In the present invention, the sugar and / or sugar alcohol blend (b) can improve the plasticity of the kneaded blend containing enteric methacrylic acid-based polymers without the use of a plasticizer. Since the present invention is free of plasticizer, various detrimental influences caused by the use of a plasticizer can be avoided. Therefore, the stability of the preparation can be improved and the dissolution properties of the drug can be easily controlled.

In the present invention, as regards the ratio of the content of the enteric polymer based on methacrylic acid to the sugar and / or sugar alcohol, the sugar and / or sugar alcohol content is usually from 0.01 to 20 18 parts by weight, preferably 0.1 to 10 parts by weight, more preferably 0.2 to 5 parts by weight, based on 1 part by weight of the enteric polymer based on methacrylic acid. The amount of sugar and / or sugar alcohol in this range is preferable because the preparation is easier to handle, the plasticity of the kneaded mixture improves and proper production (production facility) is achieved.

As regards the other sugar and / or sugar alcohol specifically described above, its melting point and the amount of water required to dissolve 1 g of sugar and / or sugar alcohol are 160 to 186 ° C and 0, 5 g for sucrose, 83 ° C and 1 g for dextrose, 102 to 105 ° C and 0.3 g for fructose and 148 to 151 ° C and is easily soluble for maltitol (Handbook of Pharmaceutical Excipients, 2001, Japan Pharmaceutical Excipients Council). (c) Drugs

Any drug can be used as long as it serves as a medicinal active ingredient to treat or prevent disease. Such drugs may be used in the form of a free body, a salt thereof, a solvate (hydrate, solvate of ethanol, etc.) or a crystalline polymorphism. Drugs suitable for use in the present invention are those in which the occurrence of side effects is reduced by the sustained release technique of the present invention to increase therapeutic efficacy. In addition, suitable drugs are those whose immediate release of the drug leads to increased therapeutic efficacy for Crohn's disease, ulcerative colitis, irritable colitis, colon cancer and similar diseases that damage the lower gastrointestinal tract. 19

The drugs may be crystalline or non-crystalline. The drugs may be water soluble or lipid soluble and may also be poorly soluble in water. The drugs are preferably weakly basic, neutral or acidic.

When poorly soluble drugs are used, pharmaceutical techniques such as nanomalization, micronisation, amorphization and the like may be used to improve the solubility of poorly soluble drugs. However, with the ethanol-wet grind technique, as described in the prior art of patent document 5, ethanol could potentially cause problems, such as crystallization or growth of drug crystals.

Examples of drugs used in the present invention include 5-amino salicylic acid, acyclovir, aspirin, acetylsalicylic acid acetaminophen, aripiprazole, ampicillin, isoniazid, ibuprofen, indomethacin, ethenadamid, enalapril, erythromycin, omeprazole, keto-conazole, salbutamol, salazo-sulfapyridine , salazopyrine, diazepam, diclofenac, diclofenac sodium, dipyridamole, cimetidine, cilostazol, simvastatin, sucralfate, sulpiride, sulfasalazine, celecoxib, tacrolimus, theophylline, tegafur, dexamethorphan, dextromethorphan, tetomilaste, terphenadine, doxorubicin, triamcinolone, tolvaptan, phosphokinin, naproxen, nifedipine, urea, sodium valproate, haloperidol, valacyclovir, paliperidone, hydrocortisone, famotidine, phenacetin, phenytoin, phenylpropanolamine, budesonide, pravastatin, pravastatin sodium, fluorouracil, prednisolone, prednisone, furosemide, probucol, vesnarinone , penicillin, perphenazine, chlorpheniramine maleate, midazolam, doxazosin mesylate, methotrexate such as morphine, ranitidine, lansoprazole, lisinopril, risperidone, lidocaine, rebamipid, levodopa, rotigotine, lovastatin, ambroxol, hydrochloride diphenhydramine, nicardipine hydrochloride, buprenorphine hydrochloride, mozavaptan hydrochloride, levocarnitine hydrochloride, acetate and the like. lorazepam, warfarin. dexamethasone hydrochloride hydrochloride hydrochloride hydrochloride hydrochloride hydrochloride hydrochloride Hydrochloride Hydrochloride Hydrochloride Hydrochloride Hydrochloride Hydrochloride Hydrochloride Hydrochloride Hydrochloride Hydrochloride Hydrochloride Hydrochloride Hydrochloride Hydrochloride Hydrochloride Hydrochloride Hydrochloride

Preferred pharmaceuticals are 5-amino salicylic acid, acyclovir, aspirin, acetylsalicylic acid, acetaminophen, aripiprazole, ibuprofen, indomethacin, ethenadamid, omeprazole, salazo-sulfapyridine, salazopyrine, diazepam, diclofenac, diclofenac sodium, dipyridamole, cilostazol, simvastatin, tacrolimus , theophylline, tegafurine, tetomylaste, doxorubicin, tolvaptan, haloperidol, paliperidone, hydrocortisone, phenytoin, budesonide, pravastatin, fluorouracil, prednisolone, prednisone, furosemide, probucol, vesnarinone, lansoprazole, risperidone, rebamipid, levodopa, rotigotine, lovastatin, carteolol hydrochloride , nicardipine hydrochloride, procaterol hydrochloride, mozavaptan hydrochloride, cortisone acetate, salbutamol sulfate, and the like. Most preferred are cilostazol, tolvaptan, phenytoin, aspirin and naproxen. The amount of these drugs contained in the pharmaceutical preparation is generally 1-90% by weight, preferably 5-80% by weight, more preferably 10 to 70% by weight. These drugs may be used alone or in combination of two or more in the pharmaceutical preparation of the present invention. 21

In the present invention, solid sustained release pharmaceutical preparations produced by the use of such drugs allow about one or two administrations per day. For example, tolvaptan has the following effects, as a vasopressin antagonist activity: vasodilator activity, hypotensive activity, inhibitory activity of saccharides in the liver, activity to inhibit the growth of mesangial cells, water diuretic activity, inhibitory activity platelet agglutination activity, vomiting inhibiting activity, urea excretion promoting activity, inhibitory activity of factor VIII secretion, heart function promoting activity, inhibitory activity of mesangial cells, saccharide production inhibitory activity in liver, aldosterone secretion inhibitory activity, endothelin production inhibitory activity, regulating activity on renin secretion, memory regulating activity, thermoregulation activity, regulating activity of prostaglandins, etc. Tolvaptan serves, advantageously, as a vasodilator, hypotensive agent, water diuretic, platelet agglutination inhibitor, urea excretion promoter, agent for heart failure, agent for renal failure, etc .; and is effective in preventing and / or treating hypertension, edema, ascites, heart failure, disorders of renal function, vasopressin para-secretion syndrome (SIADH), hepatocytosis, hypo-natremia, hypokalemia, diabetes, circulatory disorders, motion sickness, disturbed water metabolism, renal failure, various diseases associated with ischemia, etc. In addition, tolvaptan has the following effects as oxytocin antagonistic activities: uterine smooth muscle constriction inhibitory effect, milk secretion inhibitory effect, inhibitory effect on synthesis and prostaglandin secretion, and vasodilator activity; in addition, it is effective in preventing and / or treating diseases associated with oxytocin, particularly birth of premature infants, dysmenorrhea, or stopping labor in preparation for caesarean section, etc. Tolvaptan is also effective in preventing and / or treating polycystic kidney diseases. Using these drugs, the sustained release technique of the present invention can produce preparations that are administered once daily. (d) Materials for the maintenance of shape

In the present invention, the maintenance material of form (d) may be one which maintains the desired forms of the preparation, during production, in various production processes. Preferred materials are those in the form of the pharmaceutical preparations produced by the extrusion and spheronization process.

In the present invention, the desirable materials for maintaining the shape (d) are those which retain water, which increase the volume and plastic. Examples of form-maintaining materials that are used include hydroxypropylcellulose, hypromellose, methylcellulose, hydroxyethylcellulose, and water soluble cellulose materials; cellulose acetate phthalate, cellulose acetate phthalate, cellulose acetate phthalate, cellulose acetate phthalate, cellulose acetate phthalate, cellulose acetate phthalate, cellulose acetate phthalate, cellulose acetate phthalate, cellulose acetate phthalate, cellulose acetate phthalate, and cellulose acetate phthalate. Water; polyvinyl pyrrolidone, polyethylene oxide, carboxyvinyl polymers, polyvinyl alcohol (partially or fully saponified), and similar water-soluble synthetic polymers; Calcium carbonate copolymer, methacrylic acid copolymer S, methacrylic acid copolymer L, methacrylic acid copolymer LD, anhydrous methacrylic acid LD copolymer, polyvinylacetal diethylaminoacetate, methacrylic acid copolymer L, methacrylic acid copolymer and similar water insoluble synthetic polymers; wheat starch, rice starch, corn starch, potato starch, partially pregelatinized starch, pregelatinized starch, dextrin, Î ± -cyclodextrin, β-cyclodextrin, maltodextrin, isomalt, hydroxypropyl starch, carboxymethyl starch gum arabic powder, agar, agar powder, gelatin, purified gelatin, chitosan, xanthan gum, pectin, sodium alginate, locust bean gum, guar gum and compounds of similar natural polymers; stearic acid, monoglycerol stearate, carnauba wax, stearyl alcohol, cetanol, macrogol 1500, macrogol 4000, macrogol 6000 and similar low melting point substances; and others. These form maintenance materials are used alone or in combination of two or more.

Preferred form maintenance materials are water insoluble and have a minor disintegrating action. Examples of such form maintenance materials include crystalline cellulose, chitosan, sodium alginate, polycarbophil, calcium polycarbophil, etc. Crystalline cellulose is the most preferred material.

As crystalline cellulose, commercial products such as " Ceolus PH-101 ", " Ceolus PH-102 ", " Ceolus PH-301 ", " Ceolus PH-302 " and " Ceolus KG-802 " (Asahi Kasei Chemicals Corp.), " Avicel PH-200 " (FMC Corporation), " VIVAPUR 12 " (JRS), etc. The amount of these form maintenance materials contained in the pharmaceutical preparation is generally from 1 to 90% by weight, preferably 3 to 80% by weight, more preferably 5 to 50% by weight.

Other Components The pharmaceutical preparation of the present invention may contain, for example, excipients, binders, pH adjusters, absorption enhancers, lubricants, colorants, corrigents, flavors, capsules and various similar additives which may be mixed with the solid pharmaceutical preparation. These components may be mixed in the pharmaceutical preparation of the present invention in an amount which does not impair the effect of the present invention. The solid pharmaceutical preparation of the present invention is preferably produced by the extrusion process and the spheronization process. Its dosage form is preferably powders, lozenges and capsules. In addition, the solid pharmaceutical preparation of the present invention may be formed in such a way that the above powders or granules are contained in tablets, tablets similar to the separator tablets (tablets containing pellets) as described in Advancing Medication, Forefront of DDS, 2002, Yoshiharu Kaneo, p. 22, Hirokawa Publishing Co. The most preferred dosage forms of the solid pharmaceutical preparations are pellets, capsules and tablets containing pellets. Dosage forms of capsules or tablets containing pellets are advantageous because the solid pharmaceutical preparation is easier to handle and to take. In addition, from the point of view of improving the resistance and humidity measurement of the tablets, the tablet containing pellets may be film coated without impairing the effects of the present invention.

When the solid pharmaceutical preparation of the present invention takes the form of powders or granulates, the grain size of the powders and granulates is preferably 0.3-3 mm from the point of view of the production suitable for extrusion.

When the solid pharmaceutical preparation of the present invention takes the form of capsules, the size of the capsules is preferably No. 5 to 00, from the point of view of the ease of handling and taking the preparation.

When the solid pharmaceutical preparation of the present invention takes the form of a pellet-containing tablet, the tablet preferably takes the form of a circle or couplet and the diameter or major axis of the tablet is preferably in the range of 6 to 30 mm from the point of view of productivity and ease of handling and preparation.

The process of producing the solid pharmaceutical preparations of the present invention, particularly the process for the production of powders, granules and capsules, is described below but is not limited thereto. The solid pharmaceutical preparation of the present invention may be produced by various production processes. When producing powders, pellets and capsules, which are the preferred dosage forms of the present invention, the production process preferably includes at least one extrusion process. In addition to the extrusion process, the production process preferably includes a wet milling process and a spheronization process. The solid pharmaceutical preparation of the present invention is preferably produced by a wet milling process, an extrusion process, a spheronization process, a drying process and, optionally, a sieving process. In the present invention, these processes are preferably carried out in the order of wet grinding, extrusion, spheronization and drying.

When the solid pharmaceutical preparation of the present invention takes the form of a capsule, the sieving process is further followed by a method of blending a slip agent and a capsule filling process.

When the solid pharmaceutical preparation of the present invention takes the form of a pellet-containing tablet, the sieving process is followed by blending the pellets with suitable additives, lubricants and tabletting agents. In addition, the application of the coating film can be carried out after the tabletting, if necessary.

Wet Milling Process The wet milling process is the wet milling process of the above components with other components such as a bonding agent to allow the water to wet each of the components. At this point, the sugar and / or sugar alcohol of component (b) may be used as a powder or as a solution in which it is first dissolved in water. Grinding in wet media is mainly done based on a high shear granulation process. Examples of the machines used in the wet grinding process include " New Speed Kneader " (Okada Seiko Co., Ltd.), " Vertical Granulator " (Powrex Corp.), " High Speed Mixer " (Fukae Powtec Co., Ltd.), " High Speed Mixing-Type Mixer / NMG Granulator " (Nara Machinery Co., Ltd.), " Diosna Mixer Granulator " (Mutual Corporation), " Aeromatic-Fielder " (Spectrium), etc.

Extrusion process The extrusion process is the extrusion process of the crushed and wet blend obtained in the wet milling process in a screen for the production of cylindrical fibers. Extrusion machines are not limited and may be of any type, such as, for example, the type of thread feed or piston feed type. Examples of the screw type extruder include " Dome Gran DG-L1 " " Twin-Dome Gran TDG-80 " and " Twin Dome Grand TDG-110 ", (Fuji Paudal Co., Ltd.), etc. Examples of gravity feed type extruders include the type of gear roller " Gear Pelletizer GCS " (Hosokawa Micron Corp.), the type of radiation " FG type Cylindrical Extruder " (Fukae Powtec Co., Ltd.), etc.

When powders are produced, the pore size of the screen can be adjusted to 0.3 to 0.5 mm. When producing pellets and capsules, the pore size of the screen can be adjusted to 0.3 to 3 mm. 28

The spheronization process is the process of cutting cylindrical fibers obtained in the extrusion process into pieces of suitable size and the respective spheronization to provide the shape. Examples of machines used in the spheronization process include " New Speed Kneader " (new rapid crusher) (Okada Seiko Co., Ltd.), the " Marumerizer QJ " (Fuji Paudal Co., Ltd.), " CF Granulator " (CF granulator) and " Granurex GX " (Freund Co., Ltd.), etc.

Drying process The drying process is the drying process of the treated particles in the spheronization process to remove moisture. The drying may be carried out by direct heating or indirect heating. As direct heating, there may be used, for example, a tray furnace, a fluid bed dryer, etc. As indirect heating, there may be used, for example, a vacuum dryer, a microwave dryer, a far infrared dryer, etc. Specific examples of machines used in the drying process include " Glatt Fluid Bed Granulator WST " (Glatt WST fluidized bed granulator) and " Multiplex " (Powrex Corporation), " Box Aeration Parallel Flow Dryer " (parallel flow dryer and box aeration) and " Midget Dryer " (mini-drier) (Fuji Paudal Co., Ltd.), " Slit Flow FBS " (Okawara Mfg. Co., Ltd.), " Flow Dryer NFOD " (flow dryer) (Freund Corporation), " Vibration Dryer " (vibration dryer) (Chuo Kakohki Co., Ltd.), " SPHH-200 " (Tabai Spec Corp.), etc. 29

Sieving process The sieving process is the process of removing particles of a fixed grain size from the anhydrous particles. For example, a screening process is applicable to this process.

The blending process with a glidant is the process of adding a glidant to the particles after the sieving process and mixing the particles and the glidant in a homogeneous manner. For example, a mixing and diffusion process (a container rotation process) is suitable for the mixing process with a glidant.

Capsule Filling Process The capsule filling process is the process of filling capsules with the particles containing a glidant. Examples of machines used in the capsule filling process include the " LIQFIL super " (Qualicaps Co., Ltd.), the series "GKF " (Bosch Packaging Technology), the " ZANASI " and " MATIC " (IMA), etc.

EFFECT OF THE INVENTION

In the present invention, the use of sugar and / or sugar alcohol having a specific property can provide a plasticity suitable for a high-methacrylic acid-based enteric polymer blend. Therefore, it is not necessary to add a plasticizer to the solid pharmaceutical preparation of the present invention and so the following drawbacks caused by the addition of a plasticizer disappear: the combination of a plasticizer promotes metamorphosis and deformation of the enteric acid-based polymer methacrylic, making it easier to form enteric polymer films within a screen. These films can cause screen obstruction and failures of the extrusion device. In addition, the plasticizer remaining in the solid preparation promotes metamorphosis and deformation of the enteric polymer based on methacrylic acid over time. As a result, the dissolution variation of the drug over time is unavoidable.

Since the solid pharmaceutical preparation of the present invention may contain a large amount of enteric polymer based on methacrylic acid without the use of a plasticizer, the preparation has a high level of release controllability which suppresses drug release in the upper gastrointestinal tract and rapidly releases the drug into the lower gastrointestinal tract. The solid pharmaceutical preparation of the present invention contains enteric polymers based on methacrylic acid with a good pH response and thus has a high level of controllability of the release. Accordingly, there is no need for a coating process which is conducted in the production of enteric preparations, time-dependent type preparations, type-liberated preparations in the colon or the like. For this reason, according to the present invention, solid pharmaceutical preparations with the desired sustained release properties can be produced cheaply and very productively. 31

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 depicts the dissolution test of additional examples, which shows the results of the dissolution tests of Examples 24, 25 and 26. Fig. 2 represents changes in serum level following fasted administration showing tolvaptan concentration in plasma following fasted administration. FIG. 3 represents changes in serum level following administration of meals showing plasma tolvaptan concentration following meal administration. FIG. 4 represents the in vitro-in vivo correlation (level B) of additional examples schematically showing the relationship between the mean residence time (TMR) and the 50% (T5o) dissolution time of examples 24-26 (in vitro correlation -in vivo).

BEST PRACTICE FOR CARRYING OUT THIS INVENTION

EXAMPLES The present invention will be explained in more detail below with reference to the examples and comparative examples.

Example 1

Cilostazol (100 g), 15 g of Sunmalt-S (maltose monohydrate; Sanwa Cornstarch Co., Ltd.), 30 g of Eudragit S100 (methacrylic acid S copolymer Degussa AG) and 10 g of Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) in a NSK-150 rapid crusher (a mixing granulator: Okada Seiko Co., Ltd.). Thereafter, 20 g of a 5% w / v HPC-L (hydroxypropylcellulose; Nippon Soda Co., Ltd.) aqueous solution and 10 g of purified water as binder and wet mill solutions were added over 180 seconds. The comminuted product was gradually introduced into a Dome Gran DG-LL (an extruder Fuji Paudal Co., Ltd.) equipped with a dome shaped mold having a pore size of 0.6 mm and an aperture ratio of 22 , 6%. The extrusion was repeated three times at a screw speed of 40 rpm to produce fine extruded noodle-like products about 2 to 3 cm in length. Using a QJ-400 Marumerizer (a spheronizer; Fuji Paudal Co., Ltd.) equipped with a cross hatch plate in which studs were studded at 3 mm intervals, the extrudates were treated for 20 seconds at a speed of about of 1000 rpm, production wet pellets. The wet pellets were dried with a set of SPHH-200 (a tray oven; Tabai Spec Corp.) at 70 ° C for 2 to 3 hours to give the anhydrous pellets.

The fine, pasta-shaped extrudates obtained in the prior extrusion process significantly affect the quality and productivity of the solid pharmaceutical preparation of the present invention. On a scale of small amounts and since the amount of the milled product passed through a sieve is small, the pressure applied to the milled product is low during one pass and the productivity is difficult to estimate. Accordingly, when productivity is estimated based on a small amount of comminuted product, a comminuted product is repeatedly passed through a screen and the condition of the solid compositions accumulated in the space between the screen and the screw is stabilized. Under these conditions, productivity is preferentially recognized. In the following examples, a shredded product was extruded three times and the temperature of the shredded product was measured after each extrusion. The plasticity of the comminuted product was verified from these temperatures.

Using a non-contact infra-red thermometer, IR-101 (TECHNOLINE Ltd.), the temperature of the comminuted product was measured after wet milling and the temperature of the wet milled product was measured after each extrusion. The results are shown in the following table.

[Table 1]

Product crushed in moist medium Measured temperature After grinding in wet media 24.2 ° C After extrusion 31.3 ° C After 2nd extrusion 33.0 ° C After extrusion 33.0 ° C Temperature difference before and after after extrusion Δ 7.1 ° C

These results show that by mixing the maltose monohydrate can impart a moderate plasticity to a wet milled product containing a large amount of methacrylic acid copolymer S.

Example 2

Cryostazol (100 g), 15 g Erythritol 100 M (erythritol; Nikken Chemicals Co., Ltd.), 30 g Eudragit S100 (methacrylic acid copolymer S, Degussa AG) and 10 g Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) in a NSK-150 rapid crusher (a mixing granulator: Okada Seiko Co., Ltd.). Thereafter, 20 g of a 5% w / v aqueous solution of HPC-L (hydroxypropylcellulose; Nippon Soda Co., Ltd.) and 8.5 g of purified water as binder and wet grind solutions , for 160 seconds. The comminuted product was gradually introduced into a Dome Gran DG-L1 (an extruder Fuji Paudal Co., Ltd.) equipped with a dome shaped mold having a pore size of 0.6 mm and an aperture ratio of 19 , 3%. The extrusion was repeated three times at a screw speed of 40 rpm to produce fine, pasta-like extrudates about 2 to 3 cm in length. Using a QJ-400 Marumerizer (a spheronizer; Fuji Paudal Co., Ltd.) equipped with a cross hatch plate in which studs are carved at 3 mm intervals, the extrudates were treated for 15 seconds at a rotation speed of about of 1000 rpm, for the production of moist pellets. The wet pellets were dried with a set of SPHH-200 (a tray oven; Tabai Spec Corp.) at 70 ° C for 2 to 3 hours to give the anhydrous pellets.

Using a non-contact infrared thermometer, IR-101 (Technoline Ltd.), the temperature of the comminuted product was measured after grinding in wet media and the temperature of the wet comminuted product was measured after each extrusion. The results are shown in the following table.

[Table 2]

Product crushed in wet medium Measured temperature After grinding in moist medium 24.3 ° C After extrusion 31.2 ° C After 2nd extrusion 33.6 ° C After extrusion 34.6 ° C Temperature difference before and after after the extrusion Δ 6.9 ° C

These results show that by mixing erythritol a moderate plasticity can be imparted to a wet milled product containing a large amount of methacrylic acid copolymer S. 35

Example 3

Cilostazol (100 g), 15 g of Sorbitol SP (sorbitol; Nikken Chemicals Co., Ltd.), 30 g of Eudragit S100 (methacrylic acid copolymer S; Degussa AG) and 10 g of Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) in a NSK-150 rapid crusher (a mixing granulator: Okada Seiko Co., Ltd.). Thereafter, 20 g of a 5% w / v aqueous solution of HPC-L (hydroxypropylcellulose; Nippon Soda Co., Ltd.) and 8 g of purified water as binder and wet mill solutions were added for 90 seconds . The comminuted product was gradually introduced into a Dome Gran DG-L1 (an extruder Fuji Paudal Co., Ltd.) equipped with a dome shaped mold having a pore size of 0.6 mm and an aperture ratio of 22 , 6%. The extrusion was repeated three times at a screw speed of 40 rpm to produce fine extruded noodle-like products about 2 to 3 cm in length. Using a QJ-400 Marumerizer (a spheronizer; Fuji Paudal Co., Ltd.) equipped with a cross hatch plate in which studs were scored at 3 mm intervals, the extrudates were treated for 20 seconds at a speed of rotation of about 1000 rpm, producing moist pellets. The wet pellets were dried with a set of SPHH-200 (a tray oven; Tabai Spec Corp.) at 70 ° C for 2 to 3 hours to provide the anhydrous pellets.

Using a non-contact infrared thermometer, IR-101 (TECHNOLINE Ltd.), the temperature of the comminuted product was measured after grinding in wet media and the temperature of the wet comminuted product was measured after each extrusion. The results are shown in the following table.

[Table 3]

Product milled in a wet state Measured temperature After grinding in wet media 24.4 ° C After extrusion 30.3 ° C After the 2nd extrusion 34.6 ° C After the 3rd extrusion O O CO CO Difference in temperature before and after after extrusion Δ5, 9 ° C

These results show that by mixing sorbitol moderate plasticity can be imparted to a wet milled product containing a large amount of methacrylic acid copolymer S.

Example 4

Cilostazol (100 g), 15 g of Lactitol LC-1 (lactitol monohydrate, Nikken Chemicals Co., Ltd.), 30 g of Eudragit S100 (methacrylic acid copolymer S, Degussa AG) and 10 g g of Ceolus PH-301 (crystalline cellulose, Asahi Kasei Chemicals Corp.), in a NSK-150 rapid crusher (a mixing granulator: Okada Seiko Co., Ltd.). Thereafter, 20 g of a 5% w / v aqueous solution of HPC-L (hydroxypropylcellulose; Nippon Soda Co., Ltd.) and 8.5 g of purified water were added as binder and wet mill solutions 170 seconds. The comminuted product was gradually introduced into a Dome Gran DG-L1 (an extruder Fuji Paudal Co., Ltd.) equipped with a dome shaped mold having a pore size of 0.6 mm and an aperture ratio of 19 , 3%. The extrusion was repeated three times at a screw speed of 40 rpm to produce fine extruded noodle-like products about 2 to 3 cm in length. Using a Marumerizer 37 QJ-400 (a spheronizer; Fuji Paudal Co., Ltd.) equipped with a cross hatch plate in which studs were studded at 3 mm intervals, the extrudates were treated for 25 seconds at a speed of rotation of about 1000 rpm, producing moist pellets. The wet pellets were dried with a set of SPHH-200 (a tray oven; Tabai Spec Corp.) at 70 ° C for 2 to 3 hours to give the anhydrous pellets.

Using a non-contact infrared thermometer, IR-101 (TECHNOLINE Ltd.), the temperature of the comminuted product was measured after grinding in wet media and the temperature of the wet comminuted product was measured after each extrusion. The results are shown in the following table.

[Table 4]

Crushed product in wet medium Measured temperature After grinding in wet medium 23.6 ° C After extrusion 31.6 ° C After 2nd extrusion 34.6 ° C After extrusion 3rd 38.2 ° C Temperature difference before and after after extrusion Δ 8.0 ° C

These results show that by mixing the lactitol monohydrate can impart a moderate plasticity to a wet milled product containing a large amount of methacrylic acid copolymer S.

Example 5

Cilostazol (100 g), 15 g of Trehalose P (trehalose dihydrate, Nikken Chemicals Co., Ltd.), 30 g of Eudragit S100 (methacrylic acid copolymer S, Degussa AG) and 10 g of Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) in an NSK-38 150 rapid crusher (a mixing granulator: Okada Seiko Co., Ltd.). Thereafter, 20 g of a 5% aqueous solution of HPC-L ρ / v (hydroxypropylcellulose; Nippon Soda Co., Ltd.) and 8.5 g of purified water as binder and wet grinding solutions were added, for 140 seconds. The comminuted product was gradually introduced into a Dome Gran DG-L1 (an extruder Fuji Paudal Co., Ltd.) equipped with a dome shaped mold having a pore size of 0.6 mm and an aperture ratio of 19 , 3%. The extrusion was repeated three times at a screw speed of 40 rpm to produce fine extruded noodle-like products about 2 to 3 cm in length. Using a Marumerizer QJ-400 (a spheronizer; Fuji Paudal Co., Ltd.), equipped with a cross hatch plate in which pins were incised at 3 mm intervals, the extrudates were treated for 30 seconds at a speed of rotation of about 1000 rpm, producing moist pellets. The wet pellets were dried with a set of SPHH-200 (a tray oven; Tabai Spec Corp.) at 70 ° C for 2 to 3 hours to provide the anhydrous pellets.

Using a non-contact infrared thermometer, IR-101 (TECHNOLINE Ltd.), the temperature of the comminuted product was measured after grinding in wet media and the temperature of the wet comminuted product was measured after each extrusion. The results are shown in the following table.

[Table 5]

Crushed product in wet

Temperature measured 39

After grinding in wet media 23.1 ° C After extrusion 32.8 ° C After 2nd extrusion 37.8 ° C After extrusion 43.2 ° C Temperature difference before and after extrusion Δ 9, 7 ° C

These results show that by mixing the trehalose dihydrate a moderate plasticity can be imparted to a wet milled product containing a large amount of methacrylic acid copolymer S.

Example 6

Cilostazol (100 g), 15 g of Xylitol P (xylitol; Nikken Chemical Co., Ltd.), 30 g of Eudragit S100 (methacrylic acid copolymer: Degussa AG) and 10 g of Ceolus PH-301 ( Crystalline Cellulose, Asahi Kasei Chemicals Corp.) in a NSK-150 Rapid Crusher (a Mixing Granulator: Okada Seiko Co., Ltd.) · Then 20 g of a 5% aqueous solution of HPC-L / v (hydroxypropylcellulose; Nippon Soda Co., Ltd.) and 8.5 g of purified water as binder and wet grind solutions for 115 seconds. The comminuted product was gradually introduced into a Dome Gran DG-L1 (an extruder Fuji Paudal Co., Ltd.) equipped with a dome shaped mold having a pore size of 0.6 mm and an aperture ratio of 19 , 3%. The extrusion was repeated three times at a screw speed of 40 rpm to produce fine extruded noodle-like products about 2 to 3 cm in length. Using a Marumerizer QJ-400 (a spheronizer, Fuji Paudal Co., Ltd.), equipped with a cross hatch plate in which pins were incised at 3 mm intervals, the extrudates were treated for 25 seconds at a rotational speed of about 1000 rpm, producing moist pellets. Wet pellets 40 were dried with a set of SPHH-200 (a tray oven; Tabai Spec Corp.) at 70 ° C for 2 to 3 hours to give anhydrous pellets.

Using a non-contact infra-red thermometer, IR-101 (TECHNOLINE Ltd.), the temperature of the comminuted product was measured after grinding in wet media and the temperature of the wet comminuted product was measured after each extrusion. The results are shown in the following table.

[Table 6]

Crushed product in wet medium Measured temperature After grinding in wet media 23.1 ° C After extrusion 31.3 ° C After 2nd extrusion 33.3 ° C After extrusion 3 37.6 ° C Temperature difference before and after after extrusion CJ or CM 00 <1

These results show that by mixing xylitol a moderate plasticity can be imparted to a wet milled product containing a large amount of methacrylic acid copolymer S.

Comparative Example 1

Celstazol (100 g), 15 g of Wyndale Lactose 200M (lactose monohydrate, The Lactose Company of New Zealand Limited), 30 g of Eudragit S100 (methacrylic acid copolymer, Degussa AG) and 10 g of Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) in a NSK-150 rapid crusher (a mixing granulator: Okada Seiko Co., Ltd.). Thereafter, 20 g of a 5% w / v aqueous solution of HPC-L (hydroxypropylcellulose; Nippon Soda Co., Ltd.) and 10 g of purified water were added as wet binder and mill solutions for 240 seconds. The comminuted product was gradually introduced into a Dome Gran DG-L1 (an extruder Fuji Paudal Co., Ltd.) equipped with a dome shaped mold having a pore size of 0.6 mm and an aperture ratio of 22 , 6%. The extrusion was repeated twice, at a screw speed of 40 rpm; however, the third was stopped because a large load was applied to the DG-L1 and the motor current value changed significantly.

Using a non-contact infrared thermometer, IR-101 (Technoline Ltd.), the temperature of the comminuted product was measured after grinding in wet media and the temperature of the wet comminuted product was measured after each extrusion. The results are illustrated in the following table.

[Table 7]

Crushed product in wet medium Measured temperature After grinding in wet media 23.5 ° C After extrusion 51.7 ° C After 2nd extrusion 56.0 ° C After extrusion 3rd extruded Temperature difference before and after Ia extrusion Δ 28.2 ° C

These results show that mixing the lactose monohydrate does not impart a moderate plasticity to a wet milled product containing a large amount of methacrylic acid copolymer S.

Comparative Example 2

Cilostazol (100 g), 15 g of Pearlitol 50C (D-mannitol, Roquette), 30 g of Eudragit S100 (methacrylic acid copolymer Degussa AG) and 10 g Ceolus PH-301 42 (crystalline cellulose; Asahi Kasei Chemicals Corp.) in a NSK-150 rapid crusher (a blend granulator: Okada Seiko Co., Ltd.). Then, 20 g of a 5% w / v aqueous solution of HPC-L (hydroxypropylcellulose ; Nippon Soda Co., Ltd.) and 10 g of purified water as binder and wet grinding solutions for 300 seconds. The comminuted product was gradually introduced into a Dome Gran DG-L1 (an extruder Fuji Paudal Co., Ltd.) equipped with a dome shaped mold having a pore size of 0.6 mm and an aperture ratio of 19 , 3%. The extrusion was repeated twice, at a screw speed of 40 rpm; however, the third extrusion was stopped because a large load was applied to the DG-L1 and the value of the motor current changed significantly.

Using a non-contact infrared thermometer, IR-101 (Technoline Ltd.), the temperature of the comminuted product was measured after grinding in a wet medium and the temperature of the comminuted product was measured in a moist medium after each extrusion. The results are shown in the following table.

[Table 8]

Crushed product in wet medium Measured temperature After grinding in moist medium 24.3 ° C After extrusion 42.7 ° C After 2nd extrusion 53.2 ° C After extrusion 3rd extrusion Not extruded Temperature difference before and after Ia extrusion &gt; l-CO-O

These results show that mixing D-mannitol can not impart moderate plasticity to a wet milled product containing a large amount of methacrylic acid copolymer S.

Example 7 43

Cilostazol (100 g), 25 g of Sunmalt-S (maltose monohydrate; Sanwa Cornstarch Co., Ltd.), 60 g of Eudragit S100 (methacrylic acid copolymer; Degussa AG) and 20 g of Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) in a NSK-150 rapid crusher (a mixing granulator: Okada Seiko Co., Ltd.). Thereafter, 30 g of a 5% w / v aqueous solution of HPC-L (hydroxypropylcellulose; Nippon Soda Co., Ltd.) and 18 g of purified water as binder and wet grinding solutions were added for 320 seconds . The comminuted product was gradually introduced into a Dome Gran DG-L1 (an extruder Fuji Paudal Co., Ltd.) equipped with a dome shaped mold having a pore size of 0.6 mm and an aperture ratio of 22 , 6%. The extrusion was repeated three times at a screw speed of 40 rpm to produce fine extruded noodle-like products about 2 to 3 cm in length. Using a QJ-400 Marumerizer (a spheronizer; Fuji Paudal Co., Ltd.) equipped with a cross hatch plate in which studs were studded at 3 mm intervals, the extrudates were treated for 20 seconds at a speed of about of 1000 rpm, production wet pellets. The wet pellets were dried with a set of SPHH-200 (a tray oven; Tabai Spec Corp.) at 70 ° C for 2 to 3 hours to give the anhydrous pellets.

Using a non-contact infrared thermometer, IR-101 (Technoline Ltd.), the temperature of the comminuted product was measured after grinding in a wet medium and the temperature of the comminuted product was measured in a moist medium after each extrusion. The results are shown in the following table. 44 [Table 9]

Product crushed in wet media 1 measured strength After grinding in wet medium 25.6 ° C After extrusion OJ O OJ 0 O After 2nd extrusion 32.5 ° C After 3rd extrusion 34.7 ° C Temperature difference before and after the extrusion O 0 «sT <1

These results show that by mixing maltose monohydrate moderate plasticity can be imparted to a wet milled product containing a large amount of methacrylic acid copolymer S.

Example 8

Cryostazol (100 g), 25 g Erythritol 100M (erythritol; Nikken Chemicals Co., Ltd.), 60 g of Eudragit S100 (methacrylic acid copolymer; Degussa AG) and 20 g Ceolus PH-301 ( (Asahi Kasei Chemicals Corp.) in a NSK-150 quick crusher (a mixing granulator: Okada Seiko Co., Ltd.). Thereafter, 30 g of a 5% w / v aqueous solution of HPC-L (hydroxypropylcellulose; Nippon Soda Co., Ltd.) and 15 g of purified water as binder and wet grind solutions were added over 100 seconds. The comminuted product was gradually introduced into a Dome Gran DG-L1 (an extruder Fuji Paudal Co., Ltd.) equipped with a dome shaped mold having a pore size of 0.6 mm and an aperture ratio of 19 , 3%. The extrusion was repeated three times at a screw speed of 40 rpm to produce fine extruded noodle-like products about 2 to 3 cm in length. Using a QJ-400 Marumerizer (a spheronizer; Fuji Paudal Co., Ltd.) equipped with a cross hatch plate in which studs were scored at 45 mm intervals, the extrudates were treated for 30 seconds at a speed of rotation at about 1000 rpm, yielding wet pellets. The wet pellets were dried with a set of SPHH-200 (a tray oven; Tabai Spec Corp.) at 70 ° C for 2 to 3 hours to provide the anhydrous pellets.

Using a non-contact infrared thermometer, IR-101 (Technoline Ltd.), the temperature of the comminuted product was measured after grinding in a wet medium and the temperature of the comminuted product was measured in a moist medium after each extrusion. The results are shown in the following table.

[Table 10]

Crushed product in wet medium Measured temperature After grinding in wet medium 22.9 ° C After extrusion 32.6 ° C After 2nd extrusion 34.3 ° C After extrusion 3rd 38.7 ° C Temperature difference before and after after extrusion.

These results show that by mixing erythritol moderate plasticity can be imparted to a wet milled product containing a large amount of methacrylic acid copolymer S.

Example 9

Cilostazol (100 g), 25 g of Lactitol LC-1 (lactitol monohydrate, Nikken Chemicals Co., Ltd.), 60 g of Eudragit S100 (methacrylic acid copolymer Degussa AG) and 20 g of Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) in a NSK-150 rapid crusher (a mixing granulator: Okada Seiko Co., Ltd.). Thereafter, 30 g of a 5% w / v HPC-L (hydroxypropylcellulose; Nippon Soda Co., Ltd.) aqueous solution and 16.5 g of purified water as binder and wet grinding solutions for 140 seconds. The comminuted product was gradually introduced into a Dome Gran DG-LL (an extruder Fuji Paudal Co., Ltd.) equipped with a dome shaped mold having a pore size of 0.6 mm and an aperture ratio of 19 , 3%. The extrusion was repeated three times at a screw speed of 40 rpm to produce fine extruded noodle-like products about 2 to 3 cm in length. Using a QJ-400 Marumerizer (a spheronizer; Fuji Paudal Co., Ltd.) equipped with a cross hatch plate in which pins were incised at 3 mm intervals, the extrudates were treated for 30 seconds at a near rotation speed of 1000 rpm, producing moist pellets. The wet pellets were dried with a set of SPHH-200 (a tray oven; Tabai Spec Corp.) at 70 ° C for 2 to 3 hours to provide the anhydrous pellets.

Using a non-contact infrared thermometer, IR-101 (Technoline Ltd.), the temperature of the comminuted product was measured after grinding in a wet medium and the temperature of the comminuted product was measured in a moist medium after each extrusion. The results are shown in the following table.

[Table 11]

Product crushed in moist medium Temperature measured After grinding in wet medium 25.0 ° C After extrusion 31.0 ° C After 2nd extrusion 36.5 ° C After extrusion 3rd 39.5 ° C Temperature difference before and after after the extrusion O or O <1

These results show that by mixing the lactitol monohydrate can impart moderate plasticity to a wet milled product containing a large amount of methacrylic acid copolymer S.

Example 10

Cilostazol (100 g), 25 g of Sorbitol SP (sorbitol; Nikken Chemicals Co., Ltd.), 60 g of Eudragit S100 (methacrylic acid copolymer Degussa AG) and 20 g of Ceolus PH-301 ( (asahi Kasei Chemicals Corp.) in a NSK-150 rapid crusher (a mixing granulator: Okada Seiko Co., Ltd.) · 30 g of a 5% aqueous solution of HPC-L / v (hydroxypropylcellulose; Nippon Soda Co., Ltd.) and 15 g of purified water as binder and wet milling solutions for 50 seconds. The comminuted product was gradually introduced into a Dome Gran DG-L1 (an extruder Fuji Paudal Co., Ltd.) equipped with a dome shaped mold having a pore size of 0.6 mm and an aperture ratio of 22 , 6%. The extrusion was repeated three times at a screw speed of 40 rpm to produce fine extruded noodle-like products about 2 to 3 cm in length. Using a QJ-400 Marumerizer (a spheronizer; Fuji Paudal Co., Ltd.) equipped with a cross hatch plate in which studs were studded at 3 mm intervals, the extrudates were treated for 25 seconds at a speed of about of 1000 rpm, production wet pellets. The wet pellets were dried with a set of SPHH-200 (a tray oven; Tabai Spec Corp.) at 70 ° C for 2 to 3 hours to provide the anhydrous pellets.

Using a non-contact infrared thermometer, IR-101 (Technoline Ltd.), the temperature of the comminuted product was measured after grinding in a wet medium and the temperature of the comminuted product was measured in a moist medium after each extrusion . The results are shown in the following table.

[Table 12]

Product crushed in wet medium Measured temperature After grinding in wet medium 22.5 ° C After extrusion 33.0 ° C After 2nd extrusion 33.5 ° C After extrusion 3rd 35.0 ° C Temperature difference before and after after the extrusion O or LO O <1 <-1 <]

These results show that by mixing sorbitol a moderate plasticity can be imparted to a wet milled product containing a large amount of methacrylic acid copolymer S.

Example 11

Cilostazol (100 g), 25 g of Trehalose P (trehalose dihydrate, Nikken Chemicals Co., Ltd.), 60 g of Eudragit S100 (methacrylic acid copolymer S, Degussa AG) and 20 g of Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) in a NSK-150 rapid crusher (a mixing granulator: Okada Seiko Co., Ltd.). Thereafter, 30 g of a 5% w / v aqueous solution of HPC-L (hydroxypropylcellulose; Nippon Soda Co., Ltd.) and 16.5 g of purified water as binder and wet grinding solutions were added, for 110 seconds. The comminuted product was gradually introduced into a Dome Gran DG-L1 (an extruder Fuji Paudal Co., Ltd.) equipped with a dome shaped mold having a pore size of 0.6 mm and an aperture ratio of 19 , 3%. The extrusion was repeated three times at a screw speed of 40 rpm to produce fine extruded noodle-like products about 2 to 3 cm in length. Using a Marumerizer 49 QJ-400 (a spheronizer; Fuji Paudal Co., Ltd.) equipped with a cross hatch plate in which pins were incised at 3 mm intervals, the extrudates were treated for 30 seconds at a speed of rotation of about 1000 rpm, producing moist pellets. The wet pellets were dried with a set of SPHH-200 (a tray oven; Tabai Spec Corp.) at 70 ° C for 2 to 3 hours to provide the anhydrous pellets.

Using a non-contact infrared thermometer, IR-101 (Technoline Ltd.), the temperature of the comminuted product was measured after grinding in a wet medium and the temperature of the comminuted product was measured in a moist medium after each extrusion. The results are shown in the following table.

[Table 13]

Crushed product in wet medium Measured temperature After grinding in wet media 23.8 ° C After extrusion 32.5 ° C After 2nd extrusion 34.8 ° C After extrusion 3rd 36.8 ° C Temperature difference before and after after extrusion Δ8.7 ° C

These results show that by mixing the trehalose dihydrate a moderate plasticity can be imparted to a wet milled product containing a large amount of methacrylic acid copolymer S.

Example 12

Cilostazol (100 g), 25 g of Xylitol P (xylitol; Nikken Chemicals Co., Ltd.), 60 g of Eudragit S100 (methacrylic acid copolymer: Degussa AG) and 20 g of Ceolus PH-301 ( cellulose acetate, Asahi Kasei Chemicals Corp.) in a NSK-150 Rapid Crusher (a 50 Mixing Granulator, Okada Seiko Co., Ltd.). Then, 30 g of a 5% aqueous solution of HPC- (hydroxypropylcellulose; Nippon Soda Co., Ltd.) and 15 g of purified water as binder and wet grind solutions for 50 seconds. The comminuted product was gradually introduced into a Dome Gran DG-L1 (an extruder Fuji Paudal Co., Ltd.) equipped with a dome shaped mold having a pore size of 0.6 mm and an aperture ratio of 22 , 6%. The extrusion was repeated three times at a screw speed of 40 rpm to produce fine, pasta-like extrudates about 2 to 3 cm in length. Using a Marumerizer QJ-400 (a spheronizer; Fuji Paudal Co., Ltd.) equipped with a cross hatch plate into which pins were incised at 3 mm intervals, the extrudates were treated for 20 seconds at a speed of rotation of about 1000 rpm, producing moist pellets. The wet pellets were dried with a set of SPHH-200 (a tray oven; Tabai Spec Corp.) at 70 ° C for 2 to 3 hours to provide the anhydrous pellets.

Using a non-contact infrared thermometer, IR-101 (Technoline Ltd.), the temperature of the comminuted product was measured after grinding in a wet medium and the temperature of the comminuted product was measured in a moist medium after each extrusion. The results are shown in the following table.

[Table 14]

Crushed product in wet medium Measured temperature After grinding in wet medium 22.2 ° C After extrusion 29.3 ° C After 2nd extrusion 30.5 ° C After extrusion 31.6 ° C 51

Temperature difference before and after extrusion Δ 7.3 ° C

These results show that by mixing xylitol a moderate plasticity can be imparted to a wet milled product containing a large amount of methacrylic acid copolymer S.

Comparative Example 3

Cilostazol (100 g), 25 g of sucrose micronised by a hammer mill (granulated sugar CH, Ensuiko Sugar Refining Co., Ltd.), 60 g of Eudragit S100 (methacrylic acid copolymer Degussa AG) and 20 g of Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) in a NSK-150 rapid crusher (a mixing granulator: Okada Seiko Co., Ltd.). Thereafter, 30 g of a 5% w / v aqueous solution of HPC-L (hydroxypropylcellulose; Nippon Soda Co., Ltd.) and 17 g of purified water as binder and wet mill solutions were added for 90 seconds . The comminuted product was gradually introduced into a Dome Gran DG-L1 (an extruder Fuji Paudal Co., Ltd.) equipped with a dome shaped mold having a pore size of 0.6 mm and an aperture ratio of 19 , 3%. The extrusion was repeated twice, at a screw speed of 40 rpm; however, the third extrusion was stopped because a large load was applied to the DG-L1 and the value of the motor current changed significantly.

Using a non-contact infrared thermometer, IR-101 (Technoline Ltd.), the temperature of the comminuted product was measured after grinding on wet media and the temperature of the comminuted product was measured in wet media after each extrusion . The results are shown in the following table.

[Table 15]

Crushed product in moist medium Temperature measured After grinding in wet medium 23.6 ° C After extrusion 42.7 ° C After 2nd extrusion 50.3 ° C After extrusion 55.2 ° C (suspended) Difference of temperature before and after extrusion Δ 19.1 ° C

These results show that mixing the sucrose does not impart a moderate plasticity to a wet milled product containing a large amount of methacrylic acid copolymer S.

Reference example 1

Amorphous tolapaptan was prepared as follows: 7-chloro-5-hydroxy-1- [2-methyl-4- (2-methylbenzoylamino) benzoyl] -2,3,4,5-tetrahydro- Nippon Soda Co., Ltd.) in a mixed solution of dichloromethane (1390 g) and ethanol (1: 1) to give the title compound as a white powder (50 g). 350 g). The solution was treated with a spray dryer (Type ODT-8; Ohkawara Kakohki Co., Ltd.) and then immediately dried with a vacuum type dryer (LCV-232; Tabai Spec Corp) to prepare a powder amorphous (tolvaptan amorphous).

Amorphous tolylaptan (90 g, amount of tolvaptan: 60 g), prepared in Reference Example 1, 15 g of Sunmalt-S (maltose monohydrate; Sanwa Cornstarch Co., 53

Ltd.), 30 g of Eudragit S100 (methacrylic acid copolymer, Degussa AG) and 10 g of Ceolus PH-301 (crystalline cellulose, Asahi Kasei Chemicals Corp.) were mixed in a NSK-150 rapid crusher (a mixing granulator, Okada Seiko Co., Ltd.) Then 20 g of a 5% w / v aqueous solution of HPC-L (hydroxypropylcellulose; Nippon Soda Co., Ltd.) and 15 g of purified water were added as solutions of binder and wet grinding for 110 seconds. The comminuted product was gradually introduced into a Dome Gran DG-L1 (an extruder Fuji Paudal Co., Ltd.) equipped with a dome shaped mold having a pore size of 0.6 mm and an aperture ratio of 22 , 6%. The extrusion was repeated three times at a screw speed of 40 rpm to produce fine extruded noodle-like products about 2 to 3 cm in length. Using a Marumerizer QJ-400 (a spheronizer; Fuji Paudal Co., Ltd.) equipped with a cross hatch plate in which pins were incised at 3 mm intervals, the extrudates were treated for 25 seconds at a rotation speed of about 1000 rpm, producing moist pellets. The wet pellets were dried with a set of SPHH-200 (a tray oven; Tabai Spec Corp.) at 70 ° C for 2 to 3 hours to provide the anhydrous pellets.

Using a non-contact infrared thermometer, IR-101 (Technoline Ltd.), the temperature of the comminuted product was measured after grinding in a wet medium and the temperature of the comminuted product was measured in a moist medium after each extrusion. The results are shown in the following table.

[Table 16]

Crushed product in moist medium Temperature measured After grinding in wet medium 23.2 ° C 54

After extrusion O 0 O CO CM After 2nd extrusion 27.7 ° C After 3rd extrusion 29.5 ° C Temperature difference before and after extrusion &gt; CO Ol O

These results show that by mixing the maltose monohydrate, a moderate plasticity can be imparted to a wet milled product containing a large amount of methacrylic acid copolymer S.

Example 140 Amorphous tolapaptan (90 g, amount of tolvaptan: 60 g), prepared in Reference Example 1, 15 g of Erythritol 100 M (erythritol; Nikken Fine Chemicals Co., Ltd.), 30 g of Eudragit S100 (copolymer S (methacrylic acid, Degussa AG) and 10 g of Ceolus PH-301 (crystalline cellulose, Asahi Kasei Chemicals Corp.) in a NSK-150 rapid crusher (a mixing granulator, Okada Seiko Co., Ltd.). Thereafter, 20 g of a 5% w / v aqueous solution of HPC-L (hydroxypropylcellulose; Nippon Soda Co., Ltd.) and 13 g of purified water as binder and wet grind solutions were added over 90 seconds. The comminuted product was gradually introduced into a Dome Gran DG-L1 (an extruder Fuji Paudal Co., Ltd.) equipped with a dome shaped mold having a pore size of 0.6 mm and an aperture ratio of 19 , 3%. The extrusion was repeated three times at a screw speed of 40 rpm to produce fine extruded noodle-like products about 2 to 3 cm in length. Using a QJ-400 Marumerizer (a spheronizer; Fuji Paudal Co., Ltd.) equipped with a cross hatch plate in which pins were incised at 3 mm intervals, the extrudates were treated for 20 seconds at a speed of about of 1000 rpm, producing moist pellets. The wet pellets were dried with a set of SPHH-200 (a tray oven; Tabai Spec Corp.) at 70 ° C for 2 to 3 hours to provide the anhydrous pellets.

Using a non-contact infrared thermometer, IR-101 (Technoline Ltd.), the temperature of the comminuted product was measured after grinding in a wet medium and the temperature of the comminuted product was measured in a moist medium after each extrusion. The results are shown in the following table.

[Table 17]

Product crushed in wet medium Temperature measured After grinding in wet media 23.1 ° C After extrusion 29.5 ° C After 2nd extrusion 30.4 ° C After extrusion 31.8 ° C Temperature difference before and after after extrusion Δ 6.4 ° C

These results show that by mixing erythritol it can impart a moderate plasticity to a wet milled product containing a large amount of methacrylic acid copolymer S.

Example 15

The amorphous tolvaptan (90 g, tolvaptan amount: 60 g) prepared in Reference Example 1, 15 g of Lactitol LC-1 (lactitol monohydrate; Nikken Fine Chemicals Co., Ltd.) was charged with 30 g of Eudragit S100 (methacrylic acid S-co-polymer Degussa AG) and 10 g of Ceolus PH-301 (crystalline cellulose, Asahi Kasei Chemicals Corp.) in a NSK-150 rapid crusher (a mixing granulator: Okada Seiko Co., Ltd.). Thereafter, 20 g of a 5% w / v aqueous solution of HPC-L (hydroxypropylcellulose; Nippon Soda Co., Ltd.) and 13 g of purified water as binder and wet grinding solutions for 120 seconds. The comminuted product was gradually introduced into a Dome Gran DG-L1 (an extruder Fuji Paudal Co., Ltd.) equipped with a dome shaped mold having a pore size of 0.6 mm and an aperture ratio of 22 , 6%. The extrusion was repeated three times at a screw speed of 40 rpm to produce fine extruded noodle-like products about 2 to 3 cm in length. Using a QJ-400 Marumerizer (a spheronizer; Fuji Paudal Co., Ltd.) equipped with a cross hatch plate in which studs were scored at 3 mm intervals, the extrudates were treated for 30 seconds at a rotation speed of about 1000 rpm, producing moist pellets. The wet pellets were dried with a set of SPHH-200 (a tray oven; Tabai Spec Corp.) at 70 ° C for 2 to 3 hours to provide the anhydrous pellets.

Using a non-contact infrared thermometer, IR-101 (Technoline Ltd.), the temperature of the comminuted product was measured after grinding in a wet medium and the temperature of the comminuted product was measured in a moist medium after each extrusion. The results are shown in the following table.

[Table 18]

Crushed product in wet medium Measured temperature After grinding in wet medium 29.2 ° C After extrusion OJ O OJ 0 O After 2nd extrusion 31.2 ° C After extrusion 3rd 36.5 ° C Temperature difference before and after after extrusion Δ 6.1 ° C 57

These results show that by mixing the lactitol monohydrate a moderate plasticity can be imparted to a wet milled product containing a large amount of methacrylic acid copolymer S.

Example 16

The amorphous tolvaptan (90 g, tolvaptan amount: 60 g) prepared in reference example 1.15 g of Trehalose P (trehalose dihydrate; Nikken Chemicals Co., Ltd.) was charged, 30 g of Eudragit S100 (methacrylic acid copolymer S, Degussa AG) and 10 g of Ceolus PH-301 (crystalline cellulose, Asahi Kasei Chemicals Corp.) in a NSK-150 rapid crusher (a mixing granulator: Okada Seiko Co., Ltd.). Thereafter, 20 g of a 5% w / v aqueous solution of HPC-L (hydroxypropylcellulose; Nippon Soda Co., Ltd.) and 14.5 g of purified water as binder and wet grinding solutions were added, for 130 seconds. The comminuted product was gradually introduced into a Dome Gran DG-L1 (an extruder Fuji Paudal Co., Ltd.) equipped with a dome shaped mold having a pore size of 0.6 mm and an aperture ratio of 22 , 6%. The extrusion was repeated three times at a screw speed of 40 rpm to produce fine extruded noodle-like products about 2 to 3 cm in length. Using a QJ-400 Marumerizer (a spheronizer; Fuji Paudal Co., Ltd.) equipped with a cross hatch plate in which pins were incised at 3 mm intervals, the extrudates were treated for 20 seconds at a speed of about of 1000 rpm, producing moist pellets. The wet pellets were dried with a set of SPHH-200 (a tray oven; Tabai Spec Corp.) at 70 ° C for 2 to 3 hours to provide the anhydrous pellets. 58

Using a non-contact infrared thermometer, IR-101 (Technoline Ltd.), the temperature of the comminuted product was measured after grinding in a wet medium and the temperature of the comminuted product was measured in a moist medium after each extrusion. The results are shown in the following table.

[Table 19]

Product crushed in moist medium Temperature measured After grinding in wet medium 22.9 ° C After extrusion 28.1 ° C After 2nd extrusion 29.1 ° C After extrusion 31.5 ° C Temperature difference before and after after the extrusion Δ 5.2 ° C

These results show that by mixing the trehalose dihydrate a moderate plasticity can be imparted to a wet milled product containing a large amount of methacrylic acid copolymer S.

Comparative Example 4

The amorphous tolvaptan (90 g, tolvaptan amount: 60 g) prepared in Reference Example 1, 15 g of Wyndale Lactose 200M (lactose monohydrate, The Lactose Company of New Zealand Limited), 30 g of Eudragit S100 (methacrylic acid copolymer: Degussa AG) and 10 g Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) in a NSK-150 rapid crusher (a mixing granulator: Okada Seiko Co., Ltd.). Thereafter, 20 g of a 5% w / v aqueous solution of HPC-L (hydroxypropylcellulose; Nippon Soda Co., Ltd.) and 17.5 g of purified water as binder and wet grinding solutions were added, for 140 seconds. The comminuted product was gradually introduced into a Dome Gran DG-L1 (an extruder Fuji Paudal Co., Ltd.) equipped with a dome shaped mold having a pore size of 0.6 mm and an aperture ratio of 22.6%. The extrusion was repeated twice, at a screw speed of 40 rpm; however, the third extrusion was stopped because a large load was applied to the DG-L1 and the value of the motor current changed significantly.

Using a non-contact infrared thermometer, IR-101 (Technoline Ltd), the temperature of the comminuted product was measured after grinding in a wet medium and the temperature of the comminuted product was measured in a moist medium after each extrusion. The results are shown in the following table.

[Table 20]

Crushed product in wet medium Measured temperature After grinding in wet media 23.6 ° C After extrusion 42.6 ° C After 2nd extrusion 49.2 ° C After extrusion 56.5 ° C (suspended) Difference of temperature before and after the extrusion Δ 19.0 ° C

These results show that mixing the lactose monohydrate can not impart moderate plasticity to a wet milled product containing a large amount of methacrylic acid copolymer S.

Example 17

The amorphous tolvaptan (180 g, tolvaptan amount: 120 g), prepared in reference example 1, was charged with 25.8 g of Sunmalt-S (maltose monohydrate; Sanwa 60

Cornstarch Co., Ltd.), 54 g of Eudragit S100 (methacrylic acid copolymer Degussa AG) and 18 g of Ceolus PH-301 (crystalline cellulose Asahi Kasei Chemicals Corp.) in an NSK-150 rapid crusher (a granulator Mixture; Okada Seiko Co., Ltd.). Thereafter, 60 g of a 5% w / v aqueous solution of HPC-L (hydroxypropylcellulose; Nippon Soda Co., Ltd.) and 11 g of purified water as binder and wet grinding solutions were added over 180 seconds. The comminuted product was gradually introduced into a Dome Gran DG-L1 (an extruder Fuji Paudal Co., Ltd.) equipped with a dome shaped mold having a pore size of 0.8 mm and an aperture ratio of 22 , 5%. The extrusion was repeated six times at a screw speed of 40 rpm to produce fine extruded noodle-like products about 2 to 4 cm in length. Using a QJ-400 Marumerizer (a spheronizer; Fuji Paudal Co., Ltd.) equipped with a cross hatch plate in which studs were scored at 3 mm intervals, the extrudates were treated for 30 seconds at a rotational speed of about 1000 rpm, producing moist pellets. The wet pellets were dried with a set of SPHH-200 (a tray oven; Tabai Spec Corp.) at 70 ° C for 2 hours to provide the matrix pellets. The matrix pellets were sieved to a size of 600 to 1000 m. 1. Measurement of particle size distribution

The particle size of the matrix pellets (about 5 g) was measured with a Robot Shifter RPS-95 (Seishin Enterprise Co., Ltd.), based on the process of particle size measurement (anhydrous screening process) defined in the general tests of the Japanese Pharmacopoeia. The average particle size of the matrix pellets was 770 æm. 2. Measurement of decomposition

The matrix pellets (140.4 g) obtained in Example 17 were well mixed with 0.6 g of slightly anhydrous silicic acid (Adsolider-101; YK F Inc.). To this mixture was added hypromellose capsules having the size No. 3 (QUALI-V capsule Qualicaps Co., Ltd.) in an amount equivalent to 60 mg tolvaptan. Capsules containing the matrix pellets were placed in a plastic container and stored at 60 ° C for two weeks.

The matrix pellets were sprayed as mentioned above in a mortar and an amount equivalent to 30 mg tolvaptan was withdrawn. Then, methanol was added and ultrasonic waves were applied to completely destroy the pellets. Additional methanol was added and the mixture was filtered through a membrane filter having a pore size of about 0.5 μm. The resulting filtrate was applied to a LC-2010 CT (Shimadzu Corp.) high performance liquid chromatography system, with a measurement wavelength of 254 nm and mobile phase flow (acetonitrile, water and phosphoric acid in a proportion by volume of 500/500/1) of about 1 ml, to check for the presence of a particular decomposition product, which is hereinafter referred to as the decomposition product A. The concentration of the decomposition product A was calculated by the percentage area ratio (ratio of area i of the peak of the decomposition product A to the area of the tolvaptan peak). 62

Examining the concentration of the decomposition product A before and after storage, the concentration of the decomposition product A was 0.01% immediately after production and 0.02% after being stored at 60 ° C for two weeks . This revealed that the production of decomposition products was suppressed. 2. Dissolution Test

Using a DT-610 dissolution test system (Jasco Corporation), the dissolution of tolvaptan from the capsule containing the matrix pellets was evaluated according to the second dissolution test procedure (blade process) of the Japanese Pharmacopoeia . Polysorbate 80 was added to a diluted Mcllvaine buffer of pH 7.4 at a concentration of 1% v / v. This solution (900 ml) was used as a dissolution test solution. The rotation speed of the blade was 50 rpm and two wavelengths of 268 nm and 350 nm were measured at measured wavelengths. The following table indicates the dissolution rate and the difference in dissolution rate before and after storage at 60 ° C for two weeks (the &quot; dissolution rate Δ &quot; is calculated by subtracting the value after storage at 60 ° C C / two weeks to value immediately after production.

[Table 21]

Time of Immediately after After storage at 60 Sampling rate yield ° C / two weeks dissolution Δ 0.5 hour 20.9% 20.4% 0.5% 1 hour 58.4% 58.6% -0, Table 21 shows that there was a slight change in the dissolution rate of tolvaptan from the pellet-containing capsule of the matrix obtained in Example 17, immediately after production and after a storage time of two weeks / 60 ° C. It shows that the stability of the solid preparation of the present invention is clearly excellent.

Comparative Example 5

Amorphous tolapaptan (45 g, amount of tolvaptan: 30 g), prepared in the reference example 1.45 g of Pearlitol 50C (D-mannitol; Roquette), 30 g of Eudragit S100 (methacrylic acid copolymer S, Degussa AG) and 10 g of Ceolus PH-301 (Asahi Kasei Chemicals Corp.) on a NMG-1L (high shear mixing granulator of the Nara model Okada Seiko Co., Ltd.). Then, 40 g of a 1: 1 weight ratio mixture of a 4% w / v aqueous solution of HPC-L (hydroxypropylcellulose; Nippon Soda Co., Ltd.) was added as binder solutions. ) and an aqueous solution of 4% w / v polysorbate 80 (polysorbate 80 (HM); NOF Corporation) and triturated in a wet medium for 30 seconds. The comminuted product was gradually introduced into a Dome Gran DG-L1 (an extruder Fuji Paudal Co., Ltd.) equipped with a dome shaped mold having a pore size of 0.6 mm and an aperture ratio of 22 , 6%. The extrusion was repeated three times at a screw speed of 40 rpm to produce fine extruded noodle-like products about 2 to 4 cm in length. Using a QJ-400 Marumerizer (a spheronizer; Fuji Paudal Co., Ltd.) equipped with a cross hatch plate in which studs are studded at 3 mm intervals, the extrudates were treated for 60 seconds at a rotation speed of about of 1000 rpm, producing moist pellets. The wet pellets were dried with a set of SPHH-200 (a tray oven; Tabai Spec Corp.) at 70 ° C for 2 hours to obtain the matrix pellets. The matrix pellets were sieved to a size of 355 to 850 m.

The particle size distribution was measured in the same manner as in Example 17 and the mean particle size of the matrix pellets was 690 μm.

After measurement and dissolution test of the decomposition product A on the matrix pellets immediately after production, the matrix pellets were placed in an air-tight glass vial and stored for one year at room temperature. Measurement and dissolution test of the decomposition product A were carried out on these pellets after they had been stored for one year at room temperature. The matrix pellets, after one year of storage, at room temperature, were again placed in a sealed glass vessel and re-stored at 60 ° C for two weeks. Measurement and dissolution test of the decomposition product A was then measured in the matrix pellets after two weeks storage at 60 ° C. Measurement of the decomposition product A was carried out in the same manner as in Example 17. The dissolution test was done as follows.

Dissolution test

Using the DT-610 dissolution test system (Jasco Corporation), the dissolution of tolvaptan was evaluated from the matrix pellets according to the second dissolution test procedure (blades process) of the Japanese pharmacopoeia. Polysorbate 80 was added to a diluted Mcllvaine buffer of pH 7.0 at a concentration of 1% v / v. This solution (900 ml) was used as a dissolution test solution. The blade rotation speed was 100 rpm and two wavelengths of 268 nm and 350 nm were measured at measured wavelengths. Table 22 shows the result of measuring the decomposition of product A.

[Table 22]

Sample Amount of decomposition product A produced Immediately after production 0.01% After 1 year of storage at room temperature 0.13% After 2 weeks storage at 60 ° C. 0.48% Table 23 shows the dissolution test result. In the table, the &quot; dissolution rate Δ &quot; is calculated by subtracting the dissolution rate after two weeks of storage at 60 ° C from the dissolution rate after one year of storage at room temperature.

[Table 23]

Time of Immediately after Storage after 1 After 2 weeks / 60 Sampling rate at production year / room temperature Storage temperature Δ 0.5 hour 53.4% 56.2% 34.2% 22.0% 1 hour 98 , 0% 81.4% 52.9% 28.5% 2 hours 99.7% 92.7% 67.7% 25.0%

When the matrix pellets contained a plasticizer (polysorbate 80), the amount of decomposition product A produced increased significantly, while the dissolution rate significantly decreased. In addition, for one year of storage at room temperature, the amount of the produced decomposition product A is increased and the dissolution is delayed. These results 66 demonstrate that the matrix pellets obtained in comparative example 5 were remarkably lower in terms of stability of the dissolution over time.

Example 18

Amorphous tolapaptan (180 g, tolvaptan amount: 120 g), prepared in Reference Example 1, was charged to 25.8 g of Sunmalt-S (maltose monohydrate; Sanwa Cornstarch Co., Ltd.), 18 g of Eudragit S100 (methacrylic acid copolymer S, Degussa AG) and 18 g of Ceolus PH-301 (crystalline cellulose, Asahi Kasei Chemicals Corp.) in a NSK-150 rapid crusher (a mixing granulator; Okada Seiko Co., Ltd. ). Thereafter, 60 g of a 5% w / v aqueous solution of HPC-L (hydroxypropylcellulose; Nippon Soda Co., Ltd.) and 15 g of purified water as binder and wet mill solutions were added over 250 seconds. The comminuted product was gradually introduced into a Dome Gran DG-L1 (an extruder Fuji Paudal Co., Ltd.) equipped with a dome shaped mold having a pore size of 0.8 mm and an aperture ratio of 22 , 5%. The extrusion was repeated five times at a screw speed of 60 rpm to produce fine extruded noodle-like products about 2 to 3 cm in length. Using a Marumerizer QJ-400 (a spheronizer; Fuji Paudal Co., Ltd.), equipped with a cross hatch plate in which studs are scored at 3 mm intervals, the extrudates were treated for 50 seconds at a rotation speed of about 1000 rpm, producing moist pellets. The wet pellets were dried with a set of SPHH-200 (a tray oven; Tabai Spec Corp.) at 70 ° C for 2 hours to give the anhydrous pellets. The anhydrous pellets were sieved to a size of 600 to 1000 m. The anhydrous pellets contain 76.4% by weight of methacrylic acid S copolymers.

Example 19

Amorphous tolylaptan (180 g, tolvaptan amount: 120 g), prepared in reference example 1, was charged to 25.8 g of Sunmalt-S (maltose monohydrate; Sanwa Cornstarch Co., Ltd.), 30 g of Eudragit S100 (methacrylic acid copolymer Degussa AG) and 18 g of Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) in a NSK-150 rapid crusher (a mixing granulator; Okada Seiko Co., Ltd .). Thereafter, 60 g of a 5% w / v aqueous solution of HPC-L (hydroxypropylcellulose; Nippon Soda Co., Ltd.) and 8 g of purified water as binder and wet grinding solutions were added for 160 seconds . The comminuted product was gradually introduced into a Dome Gran DG-LL (an extruder Fuji Paudal Co., Ltd.) equipped with a dome shaped mold having a pore size of 0.8 mm and an aperture ratio of 22 , 5%. The extrusion was repeated six times at a screw speed of 60 rpm to produce fine extruded noodle-like products about 10 cm in length. Using a QJ-400 Marumerizer (a spheronizer; Fuji Paudal Co., Ltd.) equipped with a cross hatch plate in which studs are scored at 3 mm intervals, the extrudates were treated for 25 seconds at a rotation speed of about 1000 rpm, producing moist pellets. The wet pellets were dried with a set of SPHH-200 (a tray oven; Tabai Spec Corp.) at 70 ° C for 2 hours to give the anhydrous pellets. The squeezed pellets were sieved to a size of 600 to 1000 m. The anhydrous pellets contain 11.7% by weight of copolymers S of methacrylic acid. 68

Example 20

The amorphous tolvaptan (180 g, tolvaptan amount: 120 g), prepared in reference example 1, was charged with 25.8 g of Sunmalt-S (maltose monohydrate; Sanwa Cornstarch Co., Ltd.), 54 g of Eudragit S100 (methacrylic acid copolymer Degussa AG) and 18 g of Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) in a NSK-150 rapid crusher (a mixing granulator; Okada Seiko Co., Ltd .). Thereafter, 60 g of a 5% w / v aqueous solution of HPC-L (hydroxypropylcellulose; Nippon Soda Co., Ltd.) and 11 g of purified water as binder and wet grinding solutions were added over 180 seconds. The comminuted product was gradually introduced into a Dome Gran DG-L1 (an extruder Fuji Paudal Co., Ltd.) equipped with a dome shaped mold having a pore size of 0.8 mm and an aperture ratio of 22 , 5%. The extrusion was repeated six times at a screw speed of 60 rpm to produce fine extruded noodle-like products about 3 to 5 cm in length. Using a QJ-400 Marumerizer (a spheronizer; Fuji Paudal Co., Ltd.) equipped with a cross hatch plate in which pins were incised at 3 mm intervals, the extrudates were treated for 30 seconds at a speed of rotation of about 1000 rpm, producing moist pellets. The wet pellets were dried with a set of SPHH-200 (a tray oven; Tabai Spec Corp.) at 70 ° C for 2 hours to give the anhydrous pellets. The anhydrous pellets were sieved to a size of 600 to 1000 m. The anhydrous pellets contain 19.2% by weight of methacrylic acid S copolymers.

Comparative Example 6

Amorphous tolylaptan (90 g, tolvaptan amount: 60 g) prepared in Reference Example 1, 12.9 g of Sunmalt-S (maltose monohydrate; Sanwa Cornstarch Co., Ltd.) and 18 g of Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) in a NSK-150 rapid crusher (a mixing granulator: Okada Seiko Co., Ltd.). Thereafter, 30 g of a 5% w / v aqueous solution of HPC-L (hydroxypropylcellulose; Nippon Soda Co., Ltd.) and 6 g of purified water as binder and wet-frit solutions were added over 210 seconds. The comminuted product was gradually introduced into a Dome Gran DG-L1 (an extruder Fuji Paudal Co., Ltd.) equipped with a dome shaped mold having a pore size of 0.8 mm and an aperture ratio of 22 , 5%. Extrusion was repeated five times at a screw speed of 60 rpm to produce fine, pasta-like extrudates of about 1 to 2 cm in length. Using a Marumerizer QJ-400 (a spheronizer, Fuji Paudal Co., Ltd.), equipped with a cross hatch plate into which pins were incised at 3 mm intervals, the extrudates were treated for 60 seconds at a rotational speed of about 1000 rpm, producing moist pellets. The wet pellets were dried with a set of SPHH-200 (a tray oven; Tabai Spec Corp.) at 70 ° C for 2 hours to give the anhydrous pellets. The anhydrous pellets were sieved to a size of 600 to 1000 m. Anhydrous pellets contain no methacrylic acid S copolymer.

Dissolution test

Using the DT-610 dissolution test system (Jasco Corporation), the dissolution of 70 tolvaptan from the matrix pellets was evaluated according to the second dissolution test procedure (blades process) of the Japanese pharmacopoeia . The following test solutions 1 and 2 were used.

Test solution 1: 900 ml of a solution in which polysorbate 80 had been added to a first solution (pH 1.2) as the dissolution test solution of the 15th edition of the Japanese pharmacopoeia at a concentration of 1% w / v

Test solution 2: 900 ml of a solution in which polysorbate 80 was added to a diluted Mcllvaine buffer (pH 7.4) at a concentration of 1% w / v. The blade rotation speed for both solutions was 50 rpm and two wavelengths of 268 nm and 350 nm were used as measured wavelengths. Table 24 shows the results of the dissolution test for test solution 1. The numerical value in the table indicates the average value of the three tests.

[Table 24]

Sampling Time Comparative Example 6 Example 18 Example 19 Example 20 0.5 hour 6.5% 6.1% 6.8% 6.9% 1 hour 11.8% 10.8% 11.9% 11.6% 2 hours 19.3% 17.3% 19.8% 18.7%

Under acidic conditions of pH 1.2, there was no difference in drug dissolution of the pellets and any difference in the content of methacrylic acid polymer content was not recognized. Table 25 shows the results of the dissolution test for test solution 2. The numerical value in the table indicates the average value of the three tests.

[Table 25]

Sampling Time Comparative Example 6 Example 18 Example 19 Example 20 0.5 hour 6.3% 9.8% 12.7% 31.9% 1 hour 11.5% 18.5% 30.1% 72.1% 2 hours 18.8% 30.2% 54.3% 97.6%

In the pH regions where the methacrylic acid polymers were dissolved, the dissolution accelerated according to their amount; however, Comparative Example 8 showed a dissolution tendency exactly equal to that of the acid conditions.

Example 21

Phenytoin (100 g, Sigma-Aldrich), 60 g of Erythritol 100M (erythritol; Nikken Fine Chemicals Co., Ltd.), 15 g of Eudragit L100 (methacrylic acid copolymer, Degussa AG) and 20 g of Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) in a NSK-150 rapid crusher (a mixing granulator; Okada Seiko Co., Ltd.). Subsequently, 40 g of a 5% w / v aqueous solution of HPC-L (hydroxypropylcellulose; Nippon Soda Co., Ltd.) and 9.5 g of purified water were added as binder and wet grinding solutions , for 150 seconds. The comminuted product was gradually introduced into a Dome Gran DG-L1 (an extruder Fuji Paudal Co., Ltd.) equipped with a dome shaped mold having a pore size of 0.6 mm and an aperture ratio of 22 , 6%. The extrusion was repeated three times at a screw speed of 40 rpm to produce fine extrudates similar to 72 noodles about 2 to 3 cm in length. Using a QJ-400 Marumerizer (a spheronizer; Fuji Paudal Co., Ltd.), equipped with a cross hatch plate in which pins were incised at 3 mm intervals, the extrudates were treated for 10 seconds at a speed of rotation of about 1000 rpm, producing moist pellets. The wet pellets were dried with a set of SPHH-200 (a tray oven; Tabai Spec Corp.) at 70 ° C for 2 hours to give the anhydrous pellets.

Using a non-contact infrared thermometer, IR-101 (Technoline Ltd.), the temperature of the comminuted product was measured after grinding in a wet medium and the temperature of the comminuted product was measured in a moist medium after each extrusion. The results are shown in the following table.

[Table 26]

Product crushed in wet medium Measured temperature After grinding in wet medium 24.9 ° C After extrusion O 0% C] After the 2nd extrusion 27.1 ° C After the 3rd extrusion 27.0 ° C Temperature difference before and after extrusion Δ 1.9 ° C

Example 22

Acetylsalicylic acid, 100 g, Wako Pure Chemical Industries, Ltd.), 10 g of Lactitol LC-1 (lactitol; Nikken Fine Chemicals Co., Ltd.), 40 g of Eudragit L100D55 (S copolymer of methacrylic acid, Degussa AG) and 20 g of Ceolus PH-301 (crystalline cellulose, Asahi Kasei Chemicals Corp.) in a NSK-150 rapid crusher (a mixing granulator: Okada Seiko Co., Ltd.). Subsequently, 40 g of a 5% w / v HPC-L (hydroxypropylcellulose; Nippon Soda Co., Ltd.) aqueous solution and 9 g of purified water were added as binder and wet grinding solutions, for 130 seconds. The comminuted product was gradually introduced into a Dome Gran DG-LL (an extruder Fuji Paudal Co., Ltd.) equipped with a dome shaped mold having a pore size of 0.6 mm and an aperture ratio of 19, 3%. The extrusion was repeated three times at a screw speed of 40 rpm to produce fine extruded noodle-like products about 2 to 3 cm in length. Using a QJ-400 Marumerizer (a spheronizer; Fuji Paudal Co., Ltd.), equipped with a cross hatch plate in which pins were incised at 3 mm intervals, the extrudates were treated for 30 seconds at a rotation speed of about 1000 rpm, producing moist pellets. The wet pellets were dried with a set of SPHH-200 (a tray oven; Tabai Spec Corp.) at 70 ° C for 2 hours to give the anhydrous pellets.

Using a non-contact infrared thermometer, IR-101 (Technoline Ltd.), the temperature of the comminuted product was measured after grinding in wet media and the temperature of the comminuted product was measured in wet media after each extrusion . The results are shown in the following table.

[Table 27]

Product crushed in moist medium Temperature measured After grinding in wet medium 25.0 ° C After extrusion 32.6 ° C After 2nd extrusion 34.6 ° C After extrusion 34.6 ° C Temperature difference before and after after extrusion 47.6 ° C

Example 23

Naproxen (15 g, Sigma-Aldrich), 30 g of Trehalose P (trehalose dihydrate; Hayashibara Biochemical Laboratories, Inc.), 40 g of Eudragit L100D55 (LD copolymer of anhydrous methacrylic acid; Degussa AG) and 30 g of Ceolus PH-301 (crystalline cellulose, Asahi Kasei Chemicals Corp.) in a NSK-150 rapid crusher (a mixing granulator: Okada Seiko Co., Ltd.) · Then 20 g of an aqueous solution 5% w / v HPC-L (hydroxypropylcellulose; Nippon Soda Co., Ltd.) and 4.5 g of purified water as binder and wet mill solutions for 140 seconds. The comminuted product was gradually introduced into a Dome Gran DG-L1 (an extruder Fuji Paudal Co., Ltd.) equipped with a dome shaped mold having a pore size of 0.6 mm and an aperture ratio of 22 , 6%. The extrusion was repeated three times at a screw speed of 40 rpm to produce fine extruded noodle products about 4 cm in length. Using a QJ-400 Marumerizer (a spheronizer; Fuji Paudal Co., Ltd.) equipped with a cross hatch plate in which pins were incised at 3 mm intervals, the extrudates were treated for 30 seconds at a near rotation speed of 1000 rpm, producing moist pellets. The wet pellets were dried with a set of SPHH-200 (a tray oven; Tabai Spec Corp.) at 70 ° C for 2 hours to give the anhydrous pellets.

Using a non-contact infrared thermometer, IR-101 (Technoline Ltd.), the temperature of the comminuted product was measured after grinding in wet media and the temperature of the comminuted product was measured in wet media after each extrusion . The results are shown in the following table. 75 [Table 28]

Crushed product in wet medium Measured temperature After grinding in wet medium 25.0 ° C After extrusion 34.5 ° C After 2nd extrusion 35.9 ° C After extrusion 36.4 ° C Temperature difference before and after after extrusion Δ 9.5 ° C

Example 24

The anhydrous pellets (196 g) obtained in Example 20 were mixed with 0.8 g of Adsolider-101 (silicon dioxide; YKF Inc.) and 141 mg of the resulting granules were filled into hypromellose capsules of the size of capsule No. 3. The capsule contains 60 mg of tolvaptan.

Example 25

Amorphous tolapaptan (180 g, tolvaptan amount: 120 g), prepared in reference example 1, 25.8 g of Sunmalt-S (maltose monohydrate; Sanwa Cornstarch Co., Ltd.), 30 g of Eudragit S100 (methacrylic acid copolymer: Degussa AG) and 18 g of Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) in a NSK-150 rapid crusher (a mixing granulator; Okada Seiko Co., Ltd. ). Thereafter, 60 g of a 5% w / v aqueous solution of HPC-L (hydroxypropylcellulose; Nippon Soda Co., Ltd.) and 3 g of purified water were added as binder and wet mill solutions for 180 seconds. The comminuted product was gradually introduced into a Dome Gran DG-LL (an extruder Fuji Paudal Co., Ltd.) equipped with a dome shaped mold having a pore size of 0.8 mm and an aperture ratio of 22.5%. The extrusion was repeated four times at a screw speed of 60 rpm to produce fine, pasta-like extrudates about 2 cm in length. Using a QJ-400 Marumerizer (a spheronizer; Fuji Paudal Co., Ltd.) equipped with a cross hatch plate in which pins were incised at 3 mm intervals, the extrudates were treated for 60 seconds at a rotation speed of about of 1000 rpm, producing moist pellets. The wet pellets were dried with a set of SPHH-200 (a tray oven; Tabai Spec Corp.) at 70 ° C for 4 hours. The anhydrous pellets were sieved to produce pellets with a size of 780 m. The anhydrous pellets (179 g) were mixed with 0.8 g Adsolider-101 (silicon dioxide; YKF Inc.) and 129 mg of the resulting pellets were filled with capsule size No. 3 hypromellose capsules. The capsule contains 60 mg tolvaptan.

Example 26

The amorphous tolvaptan (180 g, tolvaptan amount: 120 g), prepared in reference example 1, was charged with 25.8 g of Sunmalt-S (maltose monohydrate; Sanwa Cornstarch Co., Ltd.), 54 g of Eudragit S100 (methacrylic acid copolymer Degussa AG) and 30 g of Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) in a NSK-150 rapid crusher (a mixing granulator; Okada Seiko Co., Ltd .). Thereafter, 60 g of a 5% w / v aqueous solution of HPC-L (hydroxypropylcellulose; Nippon Soda Co., Ltd.) and 16 g of purified water as binder and wet grinding solutions were added over 180 seconds. The comminuted product was gradually introduced into a Dome Gran DG-L1 (an extruder Fuji Paudal Co., Ltd.) equipped with a dome shaped mold having a pore size of 0.8 mm and an aperture ratio of 22.5%. The extrusion was repeated four times at a screw speed of 60 rpm to produce fine extruded noodle-like products about 2 cm in length. Using a Marumerizer QJ-400 (a spheronizer; Fuji Paudal Co., Ltd.) equipped with a cross hatch plate in which pins were incised at 3 mm intervals, the extrudates were treated for 60 seconds at a rotation speed of about 1000 rpm, producing moist pellets. The wet pellets were dried with a set of SPHH-200 (a tray oven; Tabai Spec Corp.) at 70 ° C for 4 hours. The anhydrous pellets were sieved to produce pellets with a size of 780 m. The anhydrous pellets (217 g) were mixed with 0.9 g of Adsolider-101 (silicon dioxide; YKF Inc.) and 147 mg of the resulting pellets were filled with capsule size No. 3 hypromellose capsules. The capsule contains 60 mg tolvaptan.

Dissolution test procedure

Using an NTR-6200A dissolution test system (Toyama Sangyo Co., Ltd.), the dissolution of tolvaptan from the capsule obtained in Examples 24, 25 and 26 was evaluated according to the second of the dissolution test of the Japanese pharmacopoeia. The following solution was used.

Test solution: 900 ml of a solution in which polysorbate 80 was added to a second solution (pH 6.8) as the dissolution test solution of the 15th edition of the Japanese pharmacopoeia at a concentration of 1% w / v. measured wave: λΐ, 268 mm; X2, 350 nm

Blade rotation speed: 100 rpm Number of samples: n = 6

Sampling time: 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours Calculation of time for dissolution 50% (T50) The time required to dissolve 50% tolvaptan was estimated from fig. 1.

[Table 29] 50% dissolution time, from Examples 24, 25 and 26 (T50)

Example 24 Example 25 Example 26 T50 3.72 h. 4.28 h. 7.03 h.

Oral administration test

To confirm the sustained release effect of the solid pharmaceutical preparation of the present invention, an oral administration assay was performed on healthy humans. Eighteen healthy men and women (18-45 years old) were randomly assigned to group A, group B, and group C of six subjects each. An incomplete cross-over assay of three groups and four phases was performed according to the scheme below.

[Chart 30] Dosage schedule of the oral administration assay

Group 1a step 2a step 3a step 4a step A Immediate-release tablets, fasted twice daily Example 24, fasted once daily Example 25, fasted once daily Example 25, given after one meal, once a day B Immediate release tablets. Example 26 administered in Example 24 administered in Example 24 administered after fasting twice daily fasted once daily once daily one meal once daily Immediate-release tablets administered fasted, twice daily Example 25, fasted once daily Example 26, fasted once daily Example 26, given after a meal, once daily

In the first stage, immediate-release tablets were administered to each group fasted twice daily. Two tablets containing, together, a total of 45 mg tolvaptan (one 30 mg tablet and one 15 mg tablet) were given orally in the early morning; A 15 mg tablet was then administered orally after 8 hours. The daily dosage of tolvaptan was 60 mg. In the second step, the capsules obtained in Examples 24, 25, and 26 were administered orally fasted to each group. In the third step, the capsules of the capsules were administered orally to each group in fasted form. examples 24, 25 and 26, different from those given in the second step. In the fourth step, the same capsules of examples 24, 25 and 26, as administered in the third stage, were administered orally after meals. Meals were high-fat foods according to the guidance of the US FDA (non-patent document 2). The capsules of examples 24, 25 and 26 were administered orally, within 30 minutes, after each meal. The number of cases in which the immediate-release tablets and capsules of examples 24, 25 and 26 were given as fasting was 18 and 12 respectively and the number of cases where the capsules of examples 24, 25 and 26 were given after meals was six. The compositions of the immediate release formulations are as follows.

Non-patent document 2: Guidance for Industry: Food-Effect Bioavailability and Fed 80

Bioequivalence Studies., U.S. Department of Health and Human Services, Food and Drug Administration, and Center for Drug Evaluation and Research (CDER), December 2002.

Comparative example 7: 30 mg tablets (immediate release tablet)

The amorphous tolylaptan (112.5 g; tolvaptan amount: 75 g) prepared in Reference Example 1 was charged with 185 g of lactose monohydrate, 50 g of corn starch and 50 g of crystalline cellulose and was introduced into a fluidized bed granulation dryer (Multiplex MP-01; Powrex Corporation). Fluidized bed granulation and drying were performed with 200 g of a 5% w / v aqueous solution of hydroxypropylcellulose having a hydroxypropoxyl group content of 53 to 78% by weight and granular materials were obtained. The granulated materials were mixed with 22.5 g of LH-11 (low degree of hydroxypropyl cellulose substitution) and 5 g of magnesium stearate to provide granules for the tablets. The granules were compressed with a rotary tablet machine (12HUK-AWC; Kikusui Seisakusho Ltd.) at a pressing pressure of 900 kg and at a rotation speed of 40 rpm, to obtain flat tablets of about 174 mg of weight and 8 mm in diameter containing 30 mg of tolvaptan.

Comparative example 8: 15 mg tablets (immediate release tablet)

Amorphous tolylaptan (56.3 g, tolvaptan amount: 37.6 g), prepared in reference example 1, was charged with 256.3 g of lactose monohydrate, 50 g of corn starch and 50 g of crystalline cellulose and introduced into a fluidized bed granulation dryer (Multiplex MP-01; Powrex Corporation). Fluidized bed granulation and drying were performed with 200 g of a 5% w / v aqueous solution of hydroxypropylcellulose having a hydroxypropoxyl group content of 53 to 78% by weight and granular materials were obtained. The granulated materials were mixed with 22.5 g of LH-11 (low degree of hydroxypropyl cellulose substitution) and 5 g of magnesium stearate to provide granules for the tablets. The granules were compressed with a rotary tablet machine (12HUK-AWC; Kikusui Seisakusho Ltd.) at a pressing pressure of 1000 kg and at a rotational speed of 50 rpm, to obtain flat tablets of about 180 mg of weight and 8 mm in diameter, containing 15 mg tolvaptan.

Evaluation

Blood samples were collected periodically and the tolvaptan concentration in the plasma was measured. The pharmacokinetic parameter was calculated using the WinNonlin software (see 4.0, Pharsight

Corporation) and the PSAG-CP software (Asmedica Co.). FIG. 2 shows the plasma concentration of tolvaptan following fasted administration. FIG. 3 shows the plasma concentration of tolvaptan following administration following meals.

[Table 31] PK parameter of each preparation given in the oral administration assay

Example 26, 60 82 immediate release 45 mg + 15 mg mg mg mg Administered fasted (immediate release tablet, n = 18, examples 24-26, n = 12) Cmax (ng / mL) 414 ± 96.3 375 + 168 385 ± 175 441 + 168 ASC (ng / mL) 4 840 ± 1 520 5 660 + 1 730 6 300 ± 2 510 5 959 + 1 990 Tl / 2 ) 7.6 ± 1.9 9.2 ± 1.9 10.1 ± 3.0 10.2 ± 3.1 C24h (ng / mL) 49.5 ± 26.5 88.1 ± 41.0 102 , 8 ± 38.6 113.3 ± 90.4 TMRt (h) 15.91 ± 3.64 15.84 ± 1.75 15.22 + 2.60 Administered after meal (n = 6) Cmax (ng / ml) 505 + 80.8 507 ± 185 588 + 102 ASC (ng / mL) 5 300 + 1 580 6 349 ± 2 870 7 710 + 2 430 Ti / 2 (h) 7.7 + 1.4 7, 5 ± 3,1 8,0 + 1,8 C24h (ng / mL) 63.9 + 34.9 90.3 ± 40.7 164.6 + 83.9 TMRt (h) 12.61 ± 1.90 13.91 ± 1.23 15.65 + 2.82 Fig. 4 shows, schematically, the relationship between the mean residence time (TMR) and the 50% dissolution time (T 50) of examples 24-26 (in vitro-in vivo correlation). Level B clearly indicates the relationship between TMR and T50, according to the guidance of the US FDA (non-patent document 3).

Non-patent document 3: Guidance for Industry Extended Release Oral Dosage Forms: Food-Effect Bioavailability and Fed Bioequivalence Studies, US Department of Health and Human Services, Food and Drug Administration and Center for Drug Evaluation and Research (CDER), September 1997.

Changes in color tone in test procedures of samples stored long ago 15 and 16 in during one, color conditions were

The pellets of Examples 13, 14, polyethylene bags were sealed and stored in a room, year or more. The temperature and humidity in these were not controlled. The tone changes from the 83 visually checked before and after storage. In addition, the hardness of the pellets was checked by hand.

Sample Sugar / Sugar Alcohol Color Tone Pellet Hardness Example 13 Maltose monohydrate No change No change Example 14 Erythritol No change No change Example 15 Lactitol monohydrate No change No change Example 16 Trehalose dihydrate No change No change No changes were observed in the color tone or the hardness of the granules in Examples 13 to 16.

INDUSTRIAL APPLICABILITY The solid pharmaceutical preparation of the present invention serves for many uses in the field of medicine. In particular, the solid preparation may, without the use of a plasticizer, provide an excellent plasticity to the comminuted products during the production. In addition, the preparation can overcome problems resulting from the combination of a plasticizing agent; the preparation is therefore very useful. In addition, the preparation has a high utility value as a solid, sustained release pharmaceutical preparation for oral administration.

Lisbon, April 29, 2013. 84

Claims (7)

A solid, matrix type pharmaceutical preparation characterized in that it comprises: (a) an enteric polymer based on methacrylic acid; and (b) a sugar and / or sugar alcohol, wherein 1 g of the sugar and / or sugar alcohol (b) may be dissolved in not more than 4 g of water, at a water temperature between 20 a 25 ° C. Solid pharmaceutical preparation according to claim 1, characterized in that the amount of sugar and / or sugar alcohol is from 0.1 to 10 parts by weight based on 1 part by weight of the enteric polymer based of methacrylic acid. Solid pharmaceutical preparation according to claim 1 or 2, characterized in that the sugar and / or the sugar alcohol has a melting point of 140 ° C or lower. Solid pharmaceutical preparation according to claim 1 or 2, characterized in that it is free of plasticizer. Solid pharmaceutical preparation according to claim 3, characterized in that it is free of plasticizer. A solid pharmaceutical preparation according to claim 1 or 2, characterized in that it is prepared by a production process including an extrusion process. Solid pharmaceutical preparation according to claim 3, characterized in that it is prepared by a production process including an extrusion process. Lisbon, April 29, 2013. 2